ACS Infect Dis. 2025 Jun 27. doi: 10.1021/acsinfecdis.5c00277. Online ahead of print.

ABSTRACT

Plasmid-mediated transmission of the mcr-1 gene significantly impairs the antimicrobial activity of colistin, limiting clinical therapeutic options. In this study, we evaluated the potential of bosutinib in restoring the susceptibility of colistin to mcr-1-positive drug-resistant Escherichia coli using a "drug repurposing" strategy and explored its mechanism of action to develop a new combination therapy regimen. We found that bosutinib combined with colistin significantly restored the susceptibility of mcr-1-positive E. coli to colistin and showed strong bactericidal and antibiofilm activities, confirmed by drug sensitivity assays, viable bacterial counts, and biofilm assays. Meanwhile, membrane permeability assay, reactive oxygen species (ROS) measurement, molecular docking, and SPR analysis showed that bosutinib could enhance bacterial membrane permeability, increase ROS accumulation, and directly bind to the MCR-1 protein, disrupting its resistance mechanism. Furthermore, in an infected animal model, bosutinib combined with colistin significantly increased the survival and reduced the bacterial load in tissues, confirming its in vivo antimicrobial efficacy. In conclusion, the present study reveals that bosutinib restores the antimicrobial activity of colistin through dual mechanisms: membrane permeability enhancement and direct targeting of the MCR-1 protein. Indeed, the discovery of bosutinib not only expands the application of tyrosine kinase inhibitor analogues in the field of anti-infective drugs but also provides a potentially new alternative for the clinical treatment of MCR-1-positive bacterial infections.

PMID:40576574 | DOI:10.1021/acsinfecdis.5c00277

Expert Opin Investig Drugs. 2025 Jun 27:1-12. doi: 10.1080/13543784.2025.2522075. Online ahead of print.

ABSTRACT

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and often debilitating complication of cancer treatment, affecting over 68% of treated patients. This condition is characterized by sensory deficits, neuropathic pain, and reduced quality of life. While polyvalent human immunoglobulins (IVIg) are established treatments for various immune-mediated neurological disorders, including certain inflammatory and autoimmune peripheral neuropathies, their role in CIPN remains unexplored in clinical settings.

AREAS COVERED: This review examines the neuroprotective properties of IVIg, focusing on approved indications, and explores recent preclinical evidence on the role of neuroinflammation in CIPN pathophysiology. We propose that IVIg could, based on preclinical findings, offer therapeutic benefits in managing CIPN without interfering with cancer treatments, provided that future clinical validation supports its efficacy and safety.

EXPERT OPINION: Although there is currently no clinical experience with IVIg in CIPN patients, preclinical data suggest promising therapeutic prospects. Future research is essential to elucidate CIPN mechanisms further and to determine how IVIg might contribute as a novel therapeutic strategy, ultimately improving the quality of life for cancer patients.

PMID:40575926 | DOI:10.1080/13543784.2025.2522075

In Silico Pharmacol. 2025 Jun 25;13(2):95. doi: 10.1007/s40203-025-00384-8. eCollection 2025.

ABSTRACT

The global rise in diabetes mellitus (DM) poses a significant health challenge, necessitating effective therapeutic interventions. α-Glucosidase inhibitors play a crucial role in managing postprandial hyperglycemia and reducing the risk of complications in Type 2 DM. Quantitative Structure-Activity Relationship (QSAR) modelling is critical in computational drug discovery. However, many QSAR studies on α-glucosidase inhibitors often rely on limited compound series and statistical methods, restricting their applicability across wide chemical space. Integrating machine learning (ML) into QSAR offers a promising avenue for discovering novel therapeutic compounds by handling complex information from diverse compound sets. Our study aimed to develop robust predictive models for α-glucosidase inhibitors using a dataset of 1082 compounds with known activity against intestinal α-glucosidase (maltase-glucoamylase). After data preparation, we used 626 compounds to train ML models, generating different training data of three distinct molecular representations: 2D-descriptors, 3D-descriptors, and Extended-connectivity-fingerprint (ECFP4). These models, trained on random forest and support vector machine algorithms, underwent rigorous evaluation using established metrics. Subsequently, the best-performing model was used to screen the Drugbank database, identifying potential α-glucosidase inhibitor drugs. Drug repurposing, an expedited strategy for identifying new therapeutic uses for existing drugs, holds immense potential in this regard. Molecular docking and molecular dynamics simulations further corroborated our predictions. Our results indicate that 2D descriptors and ECFP4 molecular representations outperform 3D descriptors. Furthermore, drug candidates identified from DrugBank screening exhibited promising binding interactions with α-glucosidase, supporting our ML predictions and their potential for drug repurposing.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00384-8.

PMID:40575395 | PMC:PMC12198089 | DOI:10.1007/s40203-025-00384-8

Blood Neoplasia. 2025 Apr 3;2(3):100100. doi: 10.1016/j.bneo.2025.100100. eCollection 2025 Aug.

ABSTRACT

In the last decade, newly developed drugs have significantly improved the prognosis of patients with multiple myeloma (MM). However, most patients relapse sooner or later, and thus MM remains an incurable hematological malignancy. In addition, serious adverse events occasionally hamper the continuation of treatment. Exploitation of new drugs that potentiate antitumor activities and alleviate the adverse effects of existing drugs is needed. Here, we found through drug repositioning that ambroxol hydrochloride (ambroxol) induces apoptosis of MM cells. Interestingly, turnover and reporter assays revealed that ambroxol inhibits the late stage of autophagy. Transmission electron microscopy observation also revealed that MM cells treated with ambroxol accumulated autophagic vacuoles in the cytoplasm, further supporting the inhibition of late-stage autophagy. Existing anti-MM drugs demonstrate various effects on autophagy; panobinostat, a histone deacetylase inhibitor, induces autophagy, whereas bortezomib and lenalidomide do not. When administered together, ambroxol and panobinostat exhibited a synergistic antimyeloma effect, likely due to ambroxol inhibiting the activation of panobinostat-induced autophagy while downregulating MCL-1 expression. In the KMS11 xenograft model, ambroxol significantly delayed tumor growth when administered alone; when co-administered with panobinostat, ambroxol synergistically enhanced the panobinostat-induced inhibition of tumor growth. Interestingly, concomitant use of ambroxol and panobinostat alleviated panobinostat-induced diarrhea. Gene set enrichment and pathway analyses also revealed that ambroxol increased the expression of genes related to autophagy inhibition and unfolded protein response. These results suggested that autophagy is a promising therapeutic target for MM.

PMID:40575080 | PMC:PMC12197993 | DOI:10.1016/j.bneo.2025.100100

Pharmaceutics. 2025 May 29;17(6):718. doi: 10.3390/pharmaceutics17060718.

ABSTRACT

Background/Objectives: Cutaneous melanoma is a potent neoplasm whose advancement is linked to catecholamine-induced angiogenesis through β-adrenergic receptors. Propranolol (PROP), a non-selective β-blocker, holds potential in oncology, but its systemic side effects restrict its viability. This study aims to nanoencapsulate PROP in Eudragit RL®100 polymeric nanocapsules for topical melanoma treatment. Methods: Nanocapsules were created through interfacial deposition of preformed polymer and characterized in terms of particle size, zeta potential, pH, drug content, and encapsulation efficiency. In vitro evaluations include release profile, antioxidant activity, bioadhesiveness, hemolysis, cytotoxicity, and antitumor effect on melanoma cells. Additionally, migration assays were conducted. Results: The nanocapsules displayed an acidic pH, an average size of 151 nm, and a positive zeta potential. An encapsulation efficiency of 81% was achieved, even with the hydrochloride form of the drug. The release profile exhibited sustained release of PROP, showcasing enhanced antioxidant activity in the nanoencapsulated form. The formulations also exhibited significant bioadhesion with mucin and an in vitro hemolysis rate over 50%, attributed to the cationic polymer and surfactants present. Moreover, in the cell viability assays, the NC-PROP formulations significantly reduced melanoma cell viability. In the migration assay, both the nanocapsules with and without the drug significantly inhibited cell migration, supporting the potential therapeutic benefits of these formulations. Conclusions: The nanoencapsulation of PROP in Eudragit RL®100 presents a viable strategy for topical treatment of cutaneous melanoma, enhancing release duration and reducing systemic effects. The assessments indicated distinct physical properties and substantial therapeutic potential.

PMID:40574031 | DOI:10.3390/pharmaceutics17060718

Pharmaceutics. 2025 May 27;17(6):698. doi: 10.3390/pharmaceutics17060698.

ABSTRACT

Background: Colorectal cancer (CRC) is the third most common cancer globally. Atorvastatin (ATR), a lipid-lowering drug, has shown promise as a repurposed therapeutic agent for CRC. However, its clinical application is limited by poor solubility and low oral bioavailability. This study aimed to optimize ATR-loaded chitosan-coated cubosomes using a Box-Behnken design and evaluate their potential in CRC treatment through physicochemical characterization and cell viability studies on HCT116 human CRC cells. Methods: Optimized cubosomes were characterized for particle size, zeta potential, polydispersity index (PDI), drug content, entrapment efficiency, compatibility using Fourier transform infrared spectroscopy, and in vitro release in various pH media. Cytotoxic effects were assessed using sulforhodamine B and trypan blue viability assays. Results: Uncoated cubosomes exhibited a particle size of 120.0 ± 1.66 nm, a zeta potential of -22.2 ± 1.05 mV, and a PDI of 0.136 ± 0.01. The chitosan-coated cubosomes displayed a size of 169.3 ± 4.14 nm, a zeta potential of 29.7 ± 0.814 mV, and a PDI of 0.245 ± 0.015. Entrapment efficiency and drug content were 92.1 ± 2.46% and 64.5 ± 1.58%, respectively. The ATR-loaded cubosomes demonstrated pH-dependent release, negligible at pH 1.2 and 4.5, but pronounced at pH 6.8 and 7.4, supporting colon-targeted delivery. Cell viability studies showed significant inhibition of HCT116 cells at ATR concentrations of 1 and 5 µM, with complete inhibition at higher doses. Conclusions: Chitosan-coated ATR-loaded cubosomes are promising for targeting ATR delivery to the colon. They offer enhanced anticancer activity by bypassing gastric degradation and systemic circulation, making an efficient approach to CRC treatment.

PMID:40574011 | DOI:10.3390/pharmaceutics17060698

Pharmaceuticals (Basel). 2025 Jun 13;18(6):891. doi: 10.3390/ph18060891.

ABSTRACT

Worldwide, several million people are infected with mycobacteria such as Mycobacterium tuberculosis (M. tb) or non-tuberculous mycobacteria (NTM). In 2023, 10.8 million cases and 1.25 million deaths due to M. tb were recorded. In Europe and North America, the emergence of NTM is tending to outstrip that of M. tb. Among pulmonary NTM, Mycobacterium avium complex (MAC) is the most common, accounting for 80% of NTM infections. First-line treatment requires the combination of at least three antibiotics over a long period and with different mechanisms of action to limit cross-resistance. The challenge is to discover more effective new anti-MAC molecules to reduce the duration of treatment and to overcome resistant strains. The aim of this review is to present an overview of the challenges posed by MAC infection such as side effects, reinfections and resistance mechanisms. The latest therapeutic options such as the optimized combination therapy, drug repurposing and the development of new formulations, as well as new anti-MAC compounds currently in (pre)clinical trials will also be discussed.

PMID:40573286 | DOI:10.3390/ph18060891

Pharmaceuticals (Basel). 2025 Jun 4;18(6):845. doi: 10.3390/ph18060845.

ABSTRACT

Background: Parasitic diseases, particularly Chagas disease caused by Trypanosoma cruzi, primarily affect developing countries but are now spreading to wealthier nations due to changing migration patterns. With approximately 8 to 9 million cases annually and a rise in drug resistance and side effects, there is an urgent need for new therapeutic approaches. Objectives: This study aimed to identify potential pharmacological compounds to target the TATA Binding Protein (TBP) of T. cruzi. Methods: Over eleven thousand FDA-approved pharmacological compounds were analyzed using in silico methods, including homology modeling, molecular docking, and molecular dynamics simulations. In addition, in vitro assays were conducted to assess the trypanocidal activity of promising candidates against T. cruzi epimastigotes and their selectivity toward macrophage J774.2. Results: Two compounds, DB00890 and DB07635, emerged as promising candidates, demonstrating significant potential against T. cruzi TBP. Compound DB00890 had trypanocidal activity against T. cruzi epimastigotes, with IC50 values of 70.4 µM (SI 2.84) and 37.3 µM (SI 5.36) for the NINOA and A1 strains, respectively. Conclusions: Our findings suggest DB00890 is a promising candidate for the development of new agents against Chagas disease, with the potential for targeted therapies that minimize side effects. These results provide a strong foundation for further research into novel treatments for parasitic diseases caused by T. cruzi.

PMID:40573241 | DOI:10.3390/ph18060845

Pharmaceuticals (Basel). 2025 May 25;18(6):788. doi: 10.3390/ph18060788.

ABSTRACT

Artificial intelligence (AI) is a subfield of computer science focused on developing systems that can execute tasks traditionally associated with human intelligence. AI systems work through algorithms based on rules or instructions that enable the machine to make decisions. With the advancement of science, more sophisticated AI techniques, such as machine learning and deep learning, have been developed, allowing machines to learn from large amounts of data and improve their performance over time. The pharmaceutical industry has greatly benefited from the development of this technology. AI has revolutionized drug discovery and development by enabling rapid and effective analysis of vast volumes of biological and chemical data during the identification of new therapeutic compounds. The algorithms developed can predict the efficacy, toxicity, and possible adverse effects of new drugs, optimize the steps involved in clinical trials, reduce associated time and costs, and facilitate the implementation of innovative drugs in the market, making it easier to develop precise therapies tailored to the individual genetic profile of patients. Despite significant advancements, there are still gaps in the application of AI, particularly due to the lack of comprehensive regulation. The constant evolution of this technology requires ongoing and in-depth legislative oversight to ensure its use remains safe, ethical, and free from bias. This review explores the role of AI in drug development, assessing its potential to enhance formulation, accelerate discovery, and repurpose existing medications. It highlights AI's impact across all stages, from initial research to clinical trials, emphasizing its ability to optimize processes, drive innovation, and improve therapeutic outcomes.

PMID:40573185 | DOI:10.3390/ph18060788

Molecules. 2025 Jun 19;30(12):2653. doi: 10.3390/molecules30122653.

ABSTRACT

The accumulation of senescent cells is a major contributor to aging and various age-related diseases, making developing senolytic compounds that are capable of clearing these cells an important area of research. However, progress has been hampered by the limited number of known senolytics and the incomplete understanding of their mechanisms. This study presents a powerful senolytic predictor built using phenotypic data and machine learning techniques to identify compounds with potential senolytic activity. A comprehensive training dataset consisting of 111 positive and 3951 negative compounds was curated from the literature. The dataset was used to train machine learning models, incorporating traditional molecular fingerprints, molecular descriptors, and MoLFormer molecular embeddings. By applying MoLFormer-based oversampling and testing different algorithms, it was found that the Support Vector Machine (SVM) and Multilayer Perceptron (MLP) models with MoLFormer embeddings exhibited the best performance, achieving Area Under the Curve (AUC) scores of 0.998 and 0.997, and F1 scores of 0.948 and 0.941, respectively. This senolytic predictor was then used to perform virtual screening of compounds from the DrugBank and TCMbank databases. In the DrugBank database, 98 structurally novel candidate compounds with potential senolytic activity were identified. For TCMbank, 714 potential senolytic compounds were predicted and 81 medicinal herbs with possible senolytic properties were identified. Moreover, pathway enrichment analysis revealed key targets and potential mechanisms underlying senolytic activity. In an experimental screening of predicted compounds, panaxatriol was found to exhibit senolytic activity on the etoposide-induced senescence of the IMR-90 cell line. Additionally, voclosporin was found to extend the lifespan of C. elegans more effectively than metformin, demonstrating the value of our model for drug repurposing. This study not only provides an efficient framework for discovering novel senolytic agents, but also highlights the predicted novel senolytic compounds and herbs as valuable starting points for future research into senolytic drug development.

PMID:40572616 | DOI:10.3390/molecules30122653

Biochem Pharmacol. 2025 Jun 24:117066. doi: 10.1016/j.bcp.2025.117066. Online ahead of print.

ABSTRACT

The aryl hydrocarbon receptor (AhR) was shown to be an important regulator of inflammatory processes at epithelial barriers, and is thus considered a therapeutic target for several chronic inflammatory diseases, such as inflammatory bowel disease. We aimed to identify and validate new AhR agonists that sustainably attenuate intestinal inflammation. Using a high-throughput luciferase reporter gene assay, 90 AhR ligands were identified out of 7448 approved and investigational drugs. Out of these, 15 AhR ligands were selected based on substance class, half maximal effective concentration, known toxicity and pharmacokinetic/pharmacodynamic profiles, and preclinical/clinical evaluation status for other indications. While Febuxostat, Nitazoxanide, Rabeprazole, 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester, 3-Indolepropionic acid, and Indirubin, were already known as AhR agonists, Nabumetone, Teriflunomide, Timapiprant/OC000459, and Caffeic acid phenylethyl ester have not yet been directly described in this context. Six compounds (Daidzein/Equol, as well as compounds no. 19, 22, 49, and 64, not yet disclosed due to pending patent applications) were newly described as AhR agonists. Hit compounds were studied in silico for their molecular interactions with AhR and in vitro for potential immunotoxicity and their ability to induce interleukin (IL)-10 and/or to suppress IL-1β in murine macrophages without significant cytochrome P450 1A1 induction in Caco-2 cells. Five compounds that met these criteria were functionally tested using organoid-based Transwell®-like models derived from gut biopsies. Five candidates restored the epithelial barrier, as evidenced by increased transepithelial electrical resistance and induction of the tight junction proteins claudin-1/-2 and occludin, while exhibiting anti-inflammatory effects, i.e., decreased expression of toll-like receptor 4. Out of these, one compound was selected for future in vivo preclinical studies.

PMID:40571216 | DOI:10.1016/j.bcp.2025.117066

Pharmacol Res Perspect. 2025 Aug;13(4):e70144. doi: 10.1002/prp2.70144.

ABSTRACT

Chloride channels are involved in many cellular processes, including cell volume regulation, modulation of cell excitability, and electrolyte and water secretion. Mutations of these proteins are associated with heterogeneous diseases such as myotonia, cystic fibrosis, epilepsy, deafness, lysosomal storage disease, and various kinds of renal and ophthalmic dysfunctions, also known as channelopathies. Thus, drugs targeting chloride channels may have important therapeutic applications. In this context, fenamates, commonly used for their anti-inflammatory properties, have been explored for drug repurposing in chloride channelopathies thanks to their ability to modulate multiple chloride channels. This narrative review resumes the effects of niflumic acid (NFA), flufenamic acid (FFA), mefenamic acid (MFA), meclofenamic acid (MCFA), and tolfenamic acid (TFA) on different types of chloride channel. It emerges that fenamates have a wide spectrum of activities on these channels that vary depending on multiple factors like channel isoforms, extracellular and intracellular conditions, and cell and tissue types. They may also exhibit both activating and inhibitory effects depending on their concentration. Therefore, thanks to their variegated modulatory activity on chloride channels, fenamates might be considered promising lead compounds for the development of new drug candidates that can target these altered channels involved in channelopathies. Trial Registration: EudraCT number: 2021-000708-39; ClinicalTrials.gov identifier: NCT029930005 and NCT02429570.

PMID:40568930 | DOI:10.1002/prp2.70144

Expert Opin Drug Saf. 2025 Jun 26. doi: 10.1080/14740338.2025.2525970. Online ahead of print.

ABSTRACT

INTRODUCTION: Kidney diseases, including chronic kidney disease and acute kidney injury, pose major global health challenges due to their high prevalence and impact on morbidity and mortality. Despite medical advances, there remains an urgent need for improved drug development and therapeutic strategies to treat these conditions.

AREAS COVERED: This review examines how renal transporters influence drug handling, highlighting the impact of altered transporter function on toxin accumulation, organ injury, and systemic toxicity. We also address pharmacokinetic and pharmacodynamic changes in kidney diseases, recent advances in preclinical models like microphysiological systems, emerging therapies, and biomarkers for early detection and monitoring.

EXPERT OPINION: A robust understanding of transporter function and disease-specific pharmacokinetic shifts is crucial for optimizing drug development. While MPS show promise in predicting drug responses and nephrotoxicity by more accurately simulating human kidney physiology, current hurdles include complexity, cost, and scalability. Emerging biomarkers require stringent validation to ensure specificity and reliability in kidney disease. Targeting transporters offers novel therapeutic and drug repurposing opportunities. Moving forward, refining and validating these models and biomarkers, alongside patient-tailored therapies, will improve personalized medicine and management. Attentive integration of these innovations could significantly reduce morbidity and improve outcomes worldwide for patients with kidney disease.

PMID:40568828 | DOI:10.1080/14740338.2025.2525970

Front Cell Infect Microbiol. 2025 Jun 11;15:1633037. doi: 10.3389/fcimb.2025.1633037. eCollection 2025.

NO ABSTRACT

PMID:40568702 | PMC:PMC12187863 | DOI:10.3389/fcimb.2025.1633037

F1000Res. 2025 May 7;14:481. doi: 10.12688/f1000research.163596.1. eCollection 2025.

ABSTRACT

BACKGROUND: Pleural mesothelioma is a cancer of the lung lining associated with asbestos exposure. Platinum/pemetrexed chemotherapy has been used for many years but provides little benefit and, despite recent immunotherapy advances, prognosis remains poor underpinning the need for development of novel therapeutics or drug repurposing. Fertilized hens' eggs provide a rapid and cost-effective alternative to murine models of pleural mesothelioma which are commonly used in preclinical studies, with chorioallantoic membrane (CAM) xenografts being a partial replacement for mouse flank xenografts. Here we describe methods to generate mesothelioma patient-derived xenografts on the CAM (CAM-PDX), and to subsequently assess these PDX nodules by preclinical imaging and histology.

METHODS: Fragments of surplus mesothelioma tissue obtained from patient biopsies were implanted onto the CAM on embryonic day 7 (E7), fresh or following cryopreservation, with the established PDX dissected on E14 and fixed for histological/immunohistochemical analysis. The optimal freezing method was determined by comparing tissue integrity and cellular content of cryopreserved tissue fragments with paired fresh samples via histological/immunohistochemical analyses. [ 18F]-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) was used to assess viability of PDXs in ovo.

RESULTS: Methodologies for processing, cryopreservation, re-animation, and engraftment of mesothelioma tissue fragments were established. Cryopreservation of biopsy samples and parallel processing of contiguous sections allows for assessment of mesothelioma cellularity. CAM-PDXs, generated from fresh or slow-frozen tissue, were well vascularized whilst maintaining the architecture and cellular composition of the patient tissue. Furthermore, uptake of [ 18F]-FDG following intravenous injection could be visualized and quantified.

CONCLUSIONS: The CAM is a rapid platform for engrafting patient-derived tissue, maintaining elements of the tumor microenvironment and recapitulating heterogeneity observed in mesothelioma. Combining the CAM-PDX model and FDG-PET/CT provides a quantitative in vivo platform for pre-screening of novel treatment strategies and drug combinations, with the potential for development of patient tumor avatars for predicting clinical response.

PMID:40568242 | PMC:PMC12188182 | DOI:10.12688/f1000research.163596.1

Trop Life Sci Res. 2025 Mar;36(1):223-244. doi: 10.21315/tlsr2025.36.1.12. Epub 2025 Mar 30.

ABSTRACT

In Malaysia, the study on autism spectrum disorders (ASD) is limited. Most studies only focus on gene neuroligin 3 (NLGN3), NLGN4X, neurexin 1 (NRXN1) and SH3. This study focuses on the N-methyl-D-aspartate (NMDA) that was believed to have a significant effect on ASD. In this study, potential compounds and drugs that can restore receptor function in autistic patients were analysed. This research used an effective in silico method known as drug-repurposing to discover and rediscover drugs and analyse the binding of potential compounds or drugs to the NMDA receptor. AMPA and DOCK4 were used as controls in this study. Using a trusted server, Drug ReposER, 13 potential compounds or drugs that bind to NMDAR were identified. Then, proceed to the docking of potential compounds or drugs that bind to the NMDA receptor using Autodock Vina, Autodock, Hdock and CB dock and three drugs were selected that have the best binding score to NMDA, AMPA and DOCK4. The drugs were alitretinoin, salicylic acid and indinavir, respectively. Next, molecular dynamics simulations were performed with all selected compounds to study drug-protein binding, with detailed analysis of bond stability using root-mean-square fluctuation (RMSF) oscillations. Finally, ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) predictions identify 4-androstenedione, tryptophan, carbocisteine and vitamin A as having minimal toxic effects. This study showed that alitretinoin, which was known to treat skin lesions from Kaposi's sarcoma, might have the ability to reverse the effect in ASD, particularly in NMDA receptors, potentially making a significant impact on the field of neurology and psychiatry.

PMID:40567813 | PMC:PMC12189026 | DOI:10.21315/tlsr2025.36.1.12

ACS Pharmacol Transl Sci. 2025 May 14;8(6):1567-1579. doi: 10.1021/acsptsci.4c00675. eCollection 2025 Jun 13.

ABSTRACT

The recruitment of macrophages to the intima of the arteries is a critical event in atherosclerotic progression. These macrophages accumulate excessive lipid droplets and become "foam cells", a hallmark of atherosclerosis. Most studies focus on lipid accumulation through macrophage interaction with modified monomeric low-density lipoprotein (LDL). However, in the intima, macrophages predominantly encounter aggregated LDL (agLDL), an interaction that has been studied far less. Macrophages digest agLDL and generate free cholesterol in an extracellular, acidic, and hydrolytic compartment. They form a tight seal around agLDL through actin polymerization and deliver lysosomal contents into this space in a process termed digestive exophagy. There is some evidence that inhibiting digestive exophagy to slow cholesterol accumulation in macrophages protects them from becoming foam cells and slows the progression of atherosclerotic lesions. Thus, understanding the mechanisms of digestive exophagy is critical. Here, we describe a high-content microscopy screen of a library of repurposed drugs for compounds that inhibit lysosome exocytosis during digestive exophagy. We identified many hit compounds and further characterized the effects that five of these compounds have on various aspects of digestive exophagy. In addition, three of the five compounds do not inhibit oxidized LDL-induced foam cell formation, indicating that the two pathways to foam cell formation can be targeted independently. We demonstrate that this high-content screening platform has great potential as a drug discovery tool with the ability to effectively and efficiently screen for modulators of digestive exophagy.

PMID:40567278 | PMC:PMC12186755 | DOI:10.1021/acsptsci.4c00675

Genes (Basel). 2025 Jun 14;16(6):708. doi: 10.3390/genes16060708.

ABSTRACT

BACKGROUND/OBJECTIVES: Aneuploidy is near-ubiquitous in cancer and can decrease chemotherapy efficacy while also sensitizing cells to other drugs.

METHODS: To systematically identify treatment strategies that target aneuploid cancers, data were integrated from The Cancer Genome Atlas (TCGA; 10,967 samples, 16,948 aneuploidy events) and the Broad Institute's Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) screen of 578 cancer cell lines and 4518 compounds.

RESULTS: Our analyses uncovered 37,720 significant positive and negative associations linking specific aneuploidies and treatments with patient prognosis or cell viability. Within TCGA data, 22 treatments correlated with improved 5-year survival for specific aneuploid cancers, whereas 46 were linked to worse outcomes. A complementary analysis of PRISM identified 17,946 compound-aneuploidy associations and 16,189 mechanism of action (MOA)-aneuploidy associations. Pathway-altering compounds that selectively reduce viability in cells with aneuploidy profiles were discovered, including an unexpectedly prominent number of glucocorticoid receptor agonists.

CONCLUSIONS: This integrated dataset provides a resource for designing therapeutic decision hypotheses, identifying drug-repurposing opportunities, and informing future studies aimed at targeting aneuploidy-induced vulnerabilities in cancer.

PMID:40565600 | DOI:10.3390/genes16060708

Int J Mol Sci. 2025 Jun 13;26(12):5680. doi: 10.3390/ijms26125680.

ABSTRACT

Stroke, the third leading cause of death worldwide, is a major cause of functional disability. Cerebral ischemia causes a rapid elevation of adenosine, the main neuromodulator in the brain. The inhibition of adenosine A2A receptors (A2ARs) has been introduced as a potential target in neurodegenerative disorders involving extracellular adenosine elevation. Istradefylline, a selective A2AR antagonist, has been approved for Parkinson's disease (PD) adjunctive therapy and showed neuroprotective effects in PD and Alzheimer's disease. However, the role of A2ARs in post-stroke neuronal damage and behavioral deficits remains unclear. We recently showed that A2AR antagonism prevented the adenosine-induced post-hypoxia synaptic potentiation of glutamatergic neurotransmission following the hypoxia/reperfusion of hippocampal slices. Here, we investigated the potential neuroprotective effects of istradefylline in male Sprague-Dawley rats subjected to pial vessel disruption (PVD) used to model a small-vessel stroke. Rats were treated with either a vehicle control or istradefylline (3 mg/kg i.p.) following PVD surgery for three days. Istradefylline administration prevented anxiety and depressive-like behaviors caused by PVD stroke. In addition, istradefylline significantly attenuated ischemia-induced cognitive impairment and motor deficits. Moreover, istradefylline markedly reduced hippocampal neurodegeneration, as well as GFAP/Iba-1, TNF-α, nNOS, and iNOS levels after PVD, but prevented the downregulation of anti-inflammatory markers TGF-β1 and IL-4. Together, these results suggest a molecular link between stroke and PD and that the anti-PD drug istradefylline displays translational potential for drug repurposing as a neuroprotective agent for cerebral ischemic damage.

PMID:40565142 | DOI:10.3390/ijms26125680

Int J Mol Sci. 2025 Jun 10;26(12):5541. doi: 10.3390/ijms26125541.

ABSTRACT

Alzheimer's disease (AD) is a leading cause of dementia and a growing public health concern worldwide. Despite decades of research, effective disease-modifying treatments remain elusive, partly due to limitations in current experimental models. The purpose of this review is to critically assess and compare existing murine and alternative models of AD to identify key strengths, limitations, and future directions for model development that can enhance translational relevance and therapeutic discovery. Traditional transgenic mouse models have advanced the understanding of amyloid-beta and tau pathologies, but often fail to capture the complexity of sporadic, late-onset AD. In response, alternative models-including zebrafish, Drosophila melanogaster, Caenorhabditis elegans, non-human primates, and human brain organoids-are gaining traction due to their complementary insights and diverse experimental advantages. This review also discusses innovations in genetic engineering, neuroimaging, computational modelling, and drug repurposing that are reshaping the landscape of AD research. By integrating these diverse approaches, the review advocates for a multi-model, multidisciplinary strategy to improve the predictive power, accelerate clinical translation, and inform personalised therapeutic interventions. Ethical considerations and equitable access to diagnostics and emerging treatments are also emphasised. Ultimately, this work aims to support the development of more accurate, effective, and human-relevant models to combat AD.

PMID:40565005 | DOI:10.3390/ijms26125541