Int J Mol Sci. 2025 May 9;26(10):4546. doi: 10.3390/ijms26104546.

ABSTRACT

Lung cancer is among the most common malignancies globally, is frequently associated with a poor prognosis, and is the second leading cause of cancer-related mortality in both genders. Resistance to treatment, heterogeneity, and invasiveness make lung cancer one of the most challenging tumors to combat. Drug repurposing is considered an advantageous strategy for expediting and economizing drug discovery, as it involves rebranding an existing drug for a new therapeutic use. Since depression is a prevalent psychiatric illness among individuals diagnosed with lung cancer, various selective serotonin reuptake inhibitors (SSRIs) used for the treatment of depression were examined for their possible use in lung cancer treatment as repurposed drugs. Herein, we evaluated the efficacy of SSRIs, both alone and in combination with various anticancer agents, in the treatment of lung cancer along with their mechanisms of action. The innovative approach of repurposing SSRIs offers hope by simplifying the drug discovery process and potentially revealing new therapeutic options for lung cancer. Exploring SSRIs' effects on lung cancer treatment may unlock unexpected avenues for combating this aggressive disease.

PMID:40429689 | DOI:10.3390/ijms26104546

Int J Mol Sci. 2025 May 8;26(10):4497. doi: 10.3390/ijms26104497.

ABSTRACT

Programmed death-ligand 1 (PD-L1) is a crucial immune checkpoint protein that tumors often exploit to evade immune surveillance. This study systematically screened a library of 1031 FDA-approved drugs using a high-throughput molecular dynamics approach to identify potential inhibitors targeting PD-L1. From this screening, five promising compounds-vorapaxar, delafloxacin, tenofovir disoproxil, pivmecillinam, and fursultiamine-showed significant binding affinities to PD-L1 and demonstrated cytotoxic activity against A549 lung tumor cells. These candidates were further evaluated through extended molecular dynamics simulations lasting up to 150 ns to assess their structural stability, residue fluctuations, and binding free energy. Among the identified compounds, pivmecillinam demonstrated the most favorable results, exhibiting stable binding interactions and a binding free energy of -18.01 kcal/mol, comparable to that of the known PD-L1 inhibitor BMS-1. These findings suggest that pivmecillinam has promising immunomodulatory potential and could serve as a candidate for further development in cancer immunotherapy. Overall, this study underscores the value of integrating high-throughput MD and experimental approaches for drug repositioning to identify novel therapeutic agents.

PMID:40429641 | DOI:10.3390/ijms26104497

Sci Rep. 2025 May 27;15(1):18533. doi: 10.1038/s41598-025-02999-5.

ABSTRACT

Red radish microgreens (RRM) have gained considerable attention for their promising therapeutic potential. However, the molecular mechanisms underlying their bioactivity remain inadequately characterized. This study explores the anti-inflammatory, antioxidant, and anticancer properties of RRM extract using in silico and in vivo Drosophila model analyses. The metabolite profile of the RRM extract was characterized using comprehensive metabolomics techniques, including Gas Chromatography-Mass Spectrometry (GC-MS) and Liquid Chromatography High-Resolution Mass Spectrometry (LC-HRMS). Furthermore, in silico analysis utilizing network pharmacology identified target proteins of RRM compounds associated with cancer, inflammation, and oxidative stress. Concurrently, in vivo experiments with Drosophila melanogaster PGRP-LBΔ (Dm PGRP-LBΔ) larvae was conducted to assess the extract's impact on immune and oxidative stress pathways. In silico analysis revealed that RRM compounds interacted with key proteins (AKT1, ESR1, MAPK1, SRC, TP53), modulating pathways related to cancer, inflammation, and oxidative stress. Molecular dynamics simulations reinforced the docking results by confirming robust binding of kaempferitrin to AKT1. In vivo studies showed that RRM extract suppressed immune-related genes (dptA, totA) through the NFκB and JAK-STAT pathways, reduced ROS levels, and selectively regulated antioxidant gene expression by enhancing sod1 while decreasing sod2 and cat. These results suggest RRM extract as a functional food for managing oxidative stress, inflammation, and cancer. Further research in higher organisms and clinical settings is needed.

PMID:40425671 | DOI:10.1038/s41598-025-02999-5

Curr Opin Oncol. 2025 Apr 22. doi: 10.1097/CCO.0000000000001148. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Maintenance therapy (MT), particularly antiangiogenic approaches such metronomic chemotherapy (MC), correspond to the continuous administration of low-dose anticancer agents in a context of minimal residual disease. While widely used in pediatric acute lymphoblastic leukemia for decades, MT has recently shown promise in solid tumors. Additionally, antivascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) are increasingly explored in pediatric sarcomas.

RECENT FINDINGS: This review summarize current evidence on MT efficacy in pediatric sarcomas, focusing on MC and TKIs. It examines their impact on the tumor microenvironment and cancer progression, as well as potential future applications, including standalone use or combination with targeted therapies, immunotherapies and/or drug repurposing.

SUMMARY: MT has been demonstrated to improve outcomes in specific sarcomas, especially high-risk localized rhabdomyosarcoma, and has therefore become a standard of care. Its role in other sarcomas, such as Ewing sarcoma and osteosarcoma, is under investigation. However, critical challenges remain, including optimizing drug selection, treatment duration, and patient stratification to maximize benefits.

PMID:40421977 | DOI:10.1097/CCO.0000000000001148

Phytother Res. 2025 May 26. doi: 10.1002/ptr.8490. Online ahead of print.

ABSTRACT

Growing rates of overweight and obesity worldwide call for novel approaches to treatment, and plant-derived natural products present a promising therapeutic option. Evaluate the efficacy of plant-derived natural products as dietary interventions for overweight and obesity through a systematic review and network meta-analysis. We conduct a systematic review and network meta-analysis following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. We searched from five databases and registries up to March 2024, selecting randomized controlled trials examining dietary interventions with plant-derived natural products for adults with obesity or overweight. The frequentist approach was used for the network meta-analysis, assessing 13 metabolic and obesity-related outcomes. Our review included 39 studies with 2513 participants with PROSPERO registration ID CRD42024520305. African Mango emerged as the most effective intervention, reducing body weight (MD: -10.00 kg, 95% CI: -16.74 to -3.26), waist circumference (MD: -11.70 cm, 95% CI: -17.15 to -6.25), total cholesterol (MD: -44.01 mg/dL, 95% CI: -58.95 to -29.08), triglycerides (MD: -42.65 mg/dL, 95% CI: -79.70 to -5.60), and random blood glucose (MD: -14.95 mg/dL, 95% CI: -18.60 to -11.30). Green coffee led to the largest reduction in body fat percentage (MD: -2.90%, 95% CI: -4.88 to -0.92) and BMI (MD: -3.08 kg/m2, 95% CI: -6.35 to 0.19). Ephedra was most effective in reducing fasting blood glucose (MD: -4.60 mg/dL, 95% CI: -5.49 to -3.71) and HOMA-IR (MD: -16.20, 95% CI: -18.66 to -13.74). There were too few direct comparisons between various metabolites; thus, most of the comparisons were indirect comparisons through placebo. Plant-derived natural products significantly impact obesity management, notably in body weight, waist circumference, and lipid profile reduction; however, further high-quality and rigorous studies were needed to establish the clinical efficacy of the plant-derived natural products.

PMID:40420357 | DOI:10.1002/ptr.8490

Microb Pathog. 2025 May 24:107724. doi: 10.1016/j.micpath.2025.107724. Online ahead of print.

ABSTRACT

The pandemic of COVID-19 has ignited a global race to locate effective therapies with drug repositioning emerging as a leading strategy due to its cost-effectiveness and established safety profiles. Remdesivir, Favipiravir, Hydroxychloroquine, and Chloroquine have been the focus of rigorous clinical trials to determine their therapeutic potential against SARS-CoV-2. This article delves into the innovative synthetic strategies behind these drugs, providing a blueprint for researchers navigating the complex landscape of antiviral development. Beyond synthesis, we explore the fascinating mechanisms of action: hydroxychloroquine and chloroquine elevate lysosomal pH to impede autophagy and viral replication; favipiravir, a nucleoside analogue, induces lethal mutagenesis or RNA chain termination and remdesivir disrupts viral RNA synthesis through delayed chain termination. By merging synthetic methodologies with mechanistic insights, this article offers a comprehensive resource aimed at accelerating the development of potent COVID-19 therapies and underscores the crucial part that chemistry in addressing global health emergencies. It also underscores the vital function of chemistry in addressing global health emergencies and highlights how innovative drug design and repurposing can provide rapid responses to emerging infectious diseases. This fusion of chemistry and virology not only advances our understanding of drug action but also paves the way for the discovery of new therapeutic agents crucial in future pandemics.

PMID:40419200 | DOI:10.1016/j.micpath.2025.107724

Mol Divers. 2025 May 26. doi: 10.1007/s11030-025-11214-6. Online ahead of print.

ABSTRACT

Tumor cell survival depends on the presence of oxygen and nutrients provided by existing blood vessels, particularly when cancer is in its early stage. Along with tumor growth in the vicinity of blood vessels, malignant cells require more nutrients; hence, capillary sprouting occurs from parental vessels, a process known as angiogenesis. Although multiple cellular pathways have been identified, controlling them with one single biomolecule as a multi-target inhibitor could be an attractive strategy for reducing medication side effects. Three critical pathways in angiogenesis have been identified, which are activated by the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and epidermal growth factor receptor (EGFR). This study aimed to develop a methodology to discover multi-target inhibitors among over 2000 FDA-approved drugs. Hence, a novel ensemble approach was employed, comprising classification and regression models. First, three different deep autoencoder classifications were generated for each target individually. The top 100 trained models were selected for the high-throughput virtual screening step. After that, all identified molecules with a probability of more than 0.9 in more than 70% of the models were removed to ensure accurate consideration in the regression step. Since the ultimate aim of virtual screening is to discover molecules with the highest success rate in the pharmaceutical industry, various aspects of the molecules in different assays were considered by integrating ten different regression models. In conclusion, this paper contributes to pharmaceutical sciences by introducing eleven diverse scaffolds and eight approved drugs that can potentially be used as inhibitors of angiogenesis receptors, including VEGFR, FGFR, and EGFR. Considering three target receptors simultaneously is another central concept and contribution used. This concept could increase the chance of success, while reducing the possibility of resistance to these agents.

PMID:40418485 | DOI:10.1007/s11030-025-11214-6

Arch Pharm (Weinheim). 2025 May;358(5):e70017. doi: 10.1002/ardp.70017.

ABSTRACT

Drug repurposing, which involves applying existing pharmaceuticals to new therapeutic areas, offers several advantages, including increased efficiency, reduced costs, and lower risks. The research aimed to investigate the molecular mechanisms underlying the new application of the antipsychotic drug aripiprazole (APZ) in the treatment of endometrial cancer (EC), as well as its synergistic efficacy when used in combination with progestin. The cell viability assay and proliferation assay demonstrated that APZ exerted a significant inhibitory effect on the proliferation of ISK and KLE cells. Moreover, APZ was found to induce cell apoptosis prominently by flow cytometry. Network pharmacology analysis indicated that the anti-EC effects of APZ were mediated via the epidermal growth factor receptor (EGFR)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, which was subsequently confirmed by Western blot analysis. Furthermore, APZ significantly enhanced the proliferation inhibitory effect of medroxyprogesterone acetate (MPA) against progestin-resistant KLE cells, displaying remarkable synergistic activity. These findings position APZ as a promising therapeutic candidate for EC, with potential utility both as a monotherapy and in combination with MPA, offering new avenues for EC treatment strategies.

PMID:40415233 | DOI:10.1002/ardp.70017

Australas J Dermatol. 2025 May 24. doi: 10.1111/ajd.14530. Online ahead of print.

NO ABSTRACT

PMID:40411268 | DOI:10.1111/ajd.14530

IEEE J Biomed Health Inform. 2025 May 23;PP. doi: 10.1109/JBHI.2025.3573158. Online ahead of print.

ABSTRACT

Predicting drug-disease associations is a crucial step in drug repositioning, especially with computational methods that quickly locate potential drug-disease pairs. Heterogenous network is a common tool for introducing multiple type relation information about drugs and diseases. However, the diversity of relations is ignored in most of existing methods, which makes them difficult to explore type semantic information with structure properties. Therefore, we propose a relation-centric GNN framework to encode critical association patterns. Firstly, we utilize a relation-centric graph, line graph, to represent the context of a drug-disease pair identified as the center node. The prediction problem is modeled to learn the embedding vector of the center node. Secondly, a multi-grained line graph neural network (MGLGNN) is designed to excavate fine-grained features that encapsulate local graph structures. We theoretically define a handful of typical nodes that can be regarded as high-order abstractions of relations in each type. Then, MGLGNN distills the local information and passes it to typical nodes from a global perspective. With learned multi-grained features, the center node automatically captures heterogenous relation semantics and structure patterns. Thirdly, a hierarchical contrastive learning (HCL) mechanism is proposed to ensure the quality of multi-grained features in an unsupervised way. Extensive experiments show the great potential of our model in mining drug-disease associations.

PMID:40408216 | DOI:10.1109/JBHI.2025.3573158

Med Sci (Basel). 2025 Apr 23;13(2):47. doi: 10.3390/medsci13020047.

ABSTRACT

Cancer is the second leading cause of mortality worldwide. Despite the available treatment options, a majority of cancer patients develop drug resistance, indicating the need for alternative approaches. Repurposed drugs, such as antiglycolytic and anti-microbial agents, have gained substantial attention as potential alternative strategies against different disease pathophysiologies, including lung cancer. To that end, multiple studies have suggested that the antiglycolytic dichloroacetate (DCA) and the antibiotic salinomycin (SAL) possess promising anticarcinogenic activity, attributed to their abilities to target the key metabolic enzymes, ion transport, and oncogenic signaling pathways involved in regulating cancer cell behavior, including cell survival and proliferation. We used the following searches and selection criteria. (1) Biosis and PubMed were used with the search terms dichloroacetate; salinomycin; dichloroacetate as an anticancer agent; salinomycin as an anticancer agent; dichloroacetate side effects; salinomycin side effects; salinomycin combination therapy; dichloroacetate combination therapy; and dichloroacetate or salinomycin in combination with other agents, including chemotherapy and tyrosine kinase inhibitors. (2) The exclusion criteria included not being related to the mechanisms of DCA and SAL or not focusing on their anticancer properties. (3) All the literature was sourced from peer-reviewed journals within a timeframe of 1989 to 2024. Importantly, experimental studies have demonstrated that both DCA and SAL exert promising anticarcinogenic properties, as well as having synergistic effects in combination with other therapeutic agents, against multiple cancer models. The goal of this review is to highlight the mechanistic workings and efficacy of DCA and SAL as monotherapies, and their combination with other therapeutic agents in various cancer models, with a major emphasis on non-small-cell lung cancer (NSCLC) treatment.

PMID:40407542 | DOI:10.3390/medsci13020047

Methods Protoc. 2025 May 6;8(3):48. doi: 10.3390/mps8030048.

ABSTRACT

BACKGROUND: Lafora disease (LD) is an ultra-rare and fatal neurodegenerative disorder with limited therapeutic options. Current treatments primarily address symptoms, with modest efficacy in halting disease progression, thus highlighting the urgent need for novel therapeutic approaches. Gene therapy, antisense oligonucleotides, and recombinant enzymes have recently been, and still are, under investigation. Drug repurposing may offer a promising approach to identify new, possibly effective, therapies.

METHODS: This study aims to investigate the conditions for repurposing empagliflozin, an SGLT2 (sodium/glucose cotransporter-2) inhibitor, as a potential treatment for LD and to establish a clinical protocol. Clinical phase: This 12-month prospective observational study will assess the safety and clinical efficacy of empagliflozin in two patients with early to intermediate LD stage. The primary endpoints will include changes in the severity of epilepsy and cognitive function, while the secondary endpoints will assess motor function, global function, and autonomy. Multiple clinical and instrumental evaluations (including MRI and PET with 18F-fluorodeoxyglucose) will be performed before and during treatment. Safety monitoring will include regular clinical assessments and reports of adverse events. Preclinical phase: In silico studies (using both molecular docking calculations and reverse ligand-based screening) and in vitro cell-based assays will allow us to investigate the effects of empagliflozin (and other gliflozins) on some key targets likely implicated in LD pathogenesis, such as GLUT1, GLUT3, glycogen synthase (hGYS), and glycogen phosphorylase (GP), as suggested in the literature and digital platforms for in silico target fishing.

RESULTS: The expected outcome of this study is twofold, i.e., (i) assessing the safety and tolerability of empagliflozin in LD patients and (ii) gathering preliminary data on its potential efficacy in improving clinical and neurologic features. Additionally, the in silico and in vitro studies may provide new insights into the mechanisms through which empagliflozin may exert its therapeutic effects in LD.

CONCLUSION: The findings of this study are expected to provide evidence in support of the repurposing of empagliflozin for the treatment of LD.

PMID:40407475 | DOI:10.3390/mps8030048

Br J Dermatol. 2025 May 23:ljaf195. doi: 10.1093/bjd/ljaf195. Online ahead of print.

ABSTRACT

BACKGROUND: Epidermolysis bullosa simplex (EBS) is a hereditary skin fragility disorder caused by missense pathogenic variants in KRT5 or KRT14. These variants trigger the collapse of the cytoskeleton into cytoplasmic protein aggregates, which renders the epidermis highly susceptible to mechanical stress and leads to intraepidermal blistering and loss of intercellular cohesion. Currently, no molecular therapies for EBS exist.

OBJECTIVES: Characterization of K5 or K14 mutant keratinocytes, from patients with EBS, in response to PKC412 treatment in monolayer culture and in epidermal equivalents. This clarifies the potential of PKC412 as a drug repurposing therapy approach in EBS.

METHODS: We conducted a comprehensive characterization of K5 and K14 mutant keratinocytes in response to PKC412, examining its effects on proliferation, wound closure, and apoptosis. Additionally, we evaluated the improvement of intercellular cohesion through stretch assays, epithelial sheet assays, and assessment of desmosomal organization. Finally, we investigated the efficacy of PKC412 application in both skin explants and EBS-derived epidermal equivalent cultures.

RESULTS: We demonstrated that PKC412 is effective in various keratinocytes carrying pathogenic variants associated with localized, generalized, or intermediate forms of EBS. PKC412 enhanced intercellular adhesion in both immortalized normal and EBS keratinocytes, as well as normal primary keratinocytes, and under stretch conditions. Immunoblot analyses revealed a concentration-dependent reduction in desmoplakin phosphorylation, which remained stable over the course of three days at the sites investigated. Additionally, application of PKC412 in epidermal equivalent cultures restored desmoplakin distribution in the epidermal basal layer.

CONCLUSIONS: PKC412 markedly enhanced intercellular cohesion and stress resilience in patient-derived EBS keratinocytes, both in monolayer and 3D culture systems. These findings highlight PKC412 as a promising therapeutic candidate for the treatment of EBS.

PMID:40406951 | DOI:10.1093/bjd/ljaf195

Front Immunol. 2025 May 8;16:1540018. doi: 10.3389/fimmu.2025.1540018. eCollection 2025.

ABSTRACT

BACKGROUND: Breast cancer is a heterogeneous malignancy with complex molecular characteristics, making accurate prognostication and treatment stratification particularly challenging. Emerging evidence suggests that lactylation, a novel post-translational modification, plays a crucial role in tumor progression and immune modulation.

METHODS: To address breast cancer heterogeneity, we developed a machine learning-derived lactylation signature (MLLS) using lactylation-related genes selected through random survival forest (RSF) and univariate Cox regression analyses. A total of 108 algorithmic combinations were applied across multiple datasets to construct and validate the model. Immune microenvironment characteristics were analyzed using multiple immune infiltration algorithms. Computational drug-repurposing analyses were conducted to identify potential therapeutic agents for high-risk patients.

RESULTS: The MLLS effectively stratified patients into low- and high-risk groups with significantly different prognoses. The model demonstrated robust predictive power across multiple cohorts. Immune infiltration analysis revealed that the low-risk group exhibited higher levels of immune checkpoints (e.g., PD-1, PD-L1) and greater infiltration of B cells, CD4+ T cells, and CD8+ T cells, suggesting better responsiveness to immunotherapy. In contrast, the high-risk group showed immune suppression features associated with poor prognosis. Methotrexate was computationally predicted as a potential therapeutic candidate for high-risk patients, although experimental validation remains necessary.

CONCLUSION: The MLLS represents a promising prognostic biomarker and may support personalized treatment strategies in breast cancer, particularly for identifying candidates who may benefit from immunotherapy.

PMID:40406140 | PMC:PMC12095166 | DOI:10.3389/fimmu.2025.1540018

Front Immunol. 2025 May 8;16:1587705. doi: 10.3389/fimmu.2025.1587705. eCollection 2025.

ABSTRACT

BACKGROUND: Psoriasis and Crohn's disease (CD) are chronic inflammatory diseases that involve complex immune-mediated mechanisms. Despite clinical overlap and shared genetic predispositions, the molecular pathways connecting these diseases remain incompletely understood. The present study seeks to identify shared biomarkers and therapeutic targets for psoriasis and CD.

METHODS: Differentially expressed genes (DEGs) were identified from publicly available transcriptomic datasets related to psoriasis and CD. Simultaneously, weighted gene co-expression network analysis (WGCNA) was performed to identify gene modules associated with the clinical traits of psoriasis and CD. Subsequently, biomarkers were prioritized from shared key genes by integrating protein-protein interaction (PPI) networks with machine learning models. Gene Set Enrichment Analysis (GSEA), along with Gene Ontology (GO) and KEGG pathway analyses, were performed to determine the biological significance of the identified genes. Immune infiltration analysis underscored the involvement of hub genes in immune regulation, while single-cell transcriptomic analysis revealed the cellular localization of these hub genes. Additional targeted molecular biology experiments validated the shared biomarkers. DSigDB predictions were employed to identify potential therapeutic compounds. Molecular docking simulations were performed to assess the binding affinity of the drugs to key target proteins. Finally, additional in vitro experiments were conducted to validate the therapeutic effects of the identified compounds.

RESULTS: The study identified KIF4A, DLGAP5, NCAPG, CCNB1, and CEP55 as key regulatory molecules and shared biomarkers for both diseases. GSEA and pathway analysis highlighted the importance of cell cycle regulation and immune response pathways in the comorbidities of psoriasis and CD. Immune infiltration analysis emphasized the role of hub genes in immune regulation. Furthermore, DSigDB predictions and molecular docking simulations indicated strong therapeutic potential for Etoposide, Lucanthone, and Piroxicam, with Etoposide showing the highest affinity for key targets. In cellular models, Etoposide demonstrated promising therapeutic effects by significantly downregulating the expression of psoriasis-related keratinocytes marker genes (KRT6, KRT16) and CD-related inflammatory cytokines (IL6, IL8, TNF-α), highlighting its potential in treating psoriasis and CD.

DISCUSSION: This study integrates bioinformatics, machine learning, and molecular validation to identify the shared molecular mechanisms of psoriasis and CD, uncovering novel biomarkers and potential combined therapeutic candidates. These findings provide valuable insights into potential treatment strategies for these diseases.

PMID:40406126 | PMC:PMC12095375 | DOI:10.3389/fimmu.2025.1587705

Biol Psychiatry. 2025 May 20:S0006-3223(25)01194-1. doi: 10.1016/j.biopsych.2025.05.010. Online ahead of print.

ABSTRACT

BACKGROUND: The reward circuits are crucial in treating human methamphetamine (MA) addiction, while the underlying action mechanisms may vary throughout the intervention process. This gap limits the identification of specific modulation targets and results in a "one-size-fits-all" approach. Demonstrating these specific neural signatures can inform tailored therapy and enhance precision medicine for MA addiction.

METHODS: A total of 62 MA addicts (21 females) and 57 healthy controls (16 females) were recruited. Longitudinal data were collected at the early and later stages of MA abstinence. We used probabilistic metastable substates to investigate macro-scale functional changes and established the digital twin brain model to determine key regions in abstinence from a causal, quantitative perspective. Molecular imaging, gene set, and cell-type enrichment analyses were conducted to provide a multi-scale neurobiological explanation. Computational drug repurposing analysis was performed to identify drug candidates with the potential to treat MA addiction.

RESULTS: We observed that brain regions within the reward circuits were crucial throughout the entire abstinence process. Molecular imaging, transcriptomic data, and cell-type analysis independently revealed that metabolic activities may play a more prominent role in early abstinence, while neuroplasticity is essential in both early and later abstinence. Identified putative drugs included approved medications for psychiatric symptoms, AIDS, and cancer.

CONCLUSIONS: Our work provides an integrative perspective on understanding the neural underpinnings of human MA abstinence and may inform future tailored therapies. Particularly, these findings support the stage-dependent nature of in-vivo human MA abstinence.

PMID:40403824 | DOI:10.1016/j.biopsych.2025.05.010

Biochem Biophys Res Commun. 2025 May 13;771:152001. doi: 10.1016/j.bbrc.2025.152001. Online ahead of print.

ABSTRACT

The present study focused on repurposing antifungal drugs for cancer treatment. Repurposing refers to the evaluation of an existing drug that has been used to treat a specific disease and to identify its potential to be used for other therapeutic purposes due to similarities in targets. Posaconazole is a second-generation lipophilic antifungal agent that exhibits broad-spectrum activity against various fungal infections associated with several fungal species. Posaconazole was chosen as the target drug for proteins screened through Swiss Pred to inhibit triple-negative breast cancer. The selected targets were allowed to develop a PPI network using a string database to identify bottleneck proteins. These target proteins were used for molecular docking and molecular dynamics simulations. In-silico analysis was further validated by cell viability assay in which posaconazole exhibited notable decrease in cell viability with an IC50 value of 7.2 μM in MDA-MB-231 triple negative breast cancer cell lines (TNBC). Furthermore, the migration potential of MDA-MB-231 cells following posaconazole treatment was investigated using a wound healing assay. Additionally, Posaconazole caused a notable decrease in sphere and colony formation ability. The mechanism of cell death was further analyzed using intracellular reactive oxygen species generation, mitochondrial depolarization, and cell cycle analysis. The results demonstrated that all tested variables including cell viability, migration colony formation, cell cycle analysis, ROS generation, mitochondrial depolarization and apoptosis showed statistically significant changes (p < 0.01) against the untreated control groups. The potent anticancer potential of posaconazole has opened new avenues for repurposing antifungal drugs to treat cancer.

PMID:40403682 | DOI:10.1016/j.bbrc.2025.152001

Biochem Biophys Res Commun. 2025 May 16;771:152040. doi: 10.1016/j.bbrc.2025.152040. Online ahead of print.

ABSTRACT

The clinical management of cervical cancer remains constrained by limited therapeutic options and a paucity of targeted pharmacological interventions. Drug repurposing emerges as a promising strategy to expedite oncological therapeutics development. This study systematically investigates the antineoplastic potential of HIV protease inhibitors saquinavir (SQV) and tipranavir (TPV) through multimodal mechanistic validation. In vitro analyses demonstrated dose-dependent inhibition of cervical cancer cell proliferation accompanied by significant upregulation of senescence-associated β-galactosidase (SA-β-Gal) activity. Molecular characterization revealed concomitant activation of senescence-regulatory proteins p53, p21, and p16, suggesting induction of tumor-suppressive senescence pathways. Transcriptomic profiling of inhibitor-treated SiHa cells identified critical cell cycle regulators CDK1 and CDK6, findings corroborated by molecular docking simulations revealing high-affinity binding to cyclin-dependent kinases (-32.0607 to -47.6820 kJ/mol). In vivo validation using xenograft models demonstrated comparable tumor growth inhibition to doxorubicin with preserved host viability and negligible systemic toxicity. Mechanistic integration revealed dual pathway modulation: G1-phase cell cycle arrest mediated through CDK1/6 suppression and coordinated activation of the p53/p21/p16 senescence signaling axis. These findings establish SQV and TPV as multi-targeted senotherapeutic agents, providing preclinical rationale for repurposing HIV antivirals as novel therapeutic strategy against cervical malignancies.

PMID:40403681 | DOI:10.1016/j.bbrc.2025.152040

Langenbecks Arch Surg. 2025 May 22;410(1):168. doi: 10.1007/s00423-025-03735-3.

ABSTRACT

PURPOSE: The perioperative period is characterized by psychological stress and inflammatory reactions that can contribute to disease recurrence or metastatic spread. These reactions are mediated particularly by catecholamines and prostaglandins. The PROSPER trial aimed to evaluate whether a perioperative drug repurposing with a non-selective betablocker (propranolol) and a COX-2 inhibitor (etodolac) is feasible and safe in the setting of pancreatic cancer surgery.

METHODS: Patients undergoing partial pancreatoduodenectomy for pancreatic cancer were randomized to perioperative treatment with propranolol and etodolac or placebo. Main safety endpoint was the rate of serious adverse events (SAE) and the main feasibility endpoint was adherence. Overall and disease-free survival (DFS) as well as recurrences were assessed as efficacy parameters and the trial was accompanied by a translational study.

RESULTS: The trial was prematurely closed due to slow recruitment. 26 patients were randomized, but 6 never started trial medication. Finally, 9 patients received the trial medication and 11 patients placebo. There were 6 SAE in the treatment vs. 14 in the placebo group. Adherence was lower in the treatment group, but without statistically significance. Median DFS was 16.36 months (95%-CI 1.18 - not reached) in verum vs. 11.25 (95%-CI 2.2 - 17.25) in placebo group. The rate of distant recurrences was 11.1% in verum vs. 54.5% in placebo group.

CONCLUSION: There were no safety concerns, but the trial intervention was not feasible given slow recruitment and limited adherence. However, the translational study and preliminary efficacy data revealed some promising findings, warranting further investigation.

REGISTRATION: DRKS00014054.

PMID:40402347 | DOI:10.1007/s00423-025-03735-3

Front Cell Neurosci. 2025 May 7;19:1582902. doi: 10.3389/fncel.2025.1582902. eCollection 2025.

ABSTRACT

White matter in the central nervous system comprises bundled nerve fibers myelinated by oligodendrocytes. White matter injury, characterized by the loss of oligodendrocytes and myelin, is common after ischemic brain injury, inflammatory demyelinating diseases including multiple sclerosis, and traumatic damage such as spinal cord injury. Currently, no therapies have been confirmed to promote remyelination in these diseases. Over the past decade, various reports have suggested that the anti-muscarinic drug clemastine can stimulate remyelination by oligodendrocytes. Consequently, the repurposing of clemastine as a potential treatment for a variety of neurological disorders has gained significant attention. The therapeutic effects of clemastine have been demonstrated in various animal models, and its mechanisms of action in various neurological disorders are currently being investigated. In this review, we summarize reports relating to clemastine administration for white matter injury and neurological disease and discuss the therapeutic potential of remyelination promotion.

PMID:40400770 | PMC:PMC12092462 | DOI:10.3389/fncel.2025.1582902