Front Immunol. 2025 Mar 17;16:1537428. doi: 10.3389/fimmu.2025.1537428. eCollection 2025.

ABSTRACT

Pemphigoid diseases constitute a group of organ-specific autoimmune diseases characterized and caused by autoantibodies targeting autoantigens expressed in the skin and mucous membranes. Current therapeutic options are still based on unspecific immunosuppression that is associated with severe adverse events. Biologics, targeting the IL4-pathway or IgE are expected to change the treatment landscape of pemphigoid diseases. However, clinical studies demonstrated that targeting these pathways alone is most likely not sufficient to meet patient and healthcare partitioners expectations. Hence, model systems are needed to identify and validate novel therapeutic targets in pemphigoid diseases. These include pre-clinical animal models, in vitro and ex vivo model systems, hypothesis-driven drug repurposing, as well as exploitation of real-world-data. In this review, we will highlight the medical need for pemphigoid diseases, and in-depth discuss the advantages and disadvantages of the available pemphigoid disease model systems. Ultimately, we discuss how rapid translation can be achieved for the benefit of the patients.

PMID:40165962 | PMC:PMC11955494 | DOI:10.3389/fimmu.2025.1537428

Neuroscience. 2025 Mar 29:S0306-4522(25)00266-0. doi: 10.1016/j.neuroscience.2025.03.064. Online ahead of print.

ABSTRACT

Drug repositioning or drug reprofiling, involves identifying novel indications for approved and previously abandoned drugs in the treatment of other diseases. The traditional drug discovery process is tedious, time-consuming, risky, and challenging. Fortunately, the inception of the drug repositioning concept has expedited the process by using compounds with established safety profiles in humans, and thereby significantly reducing costs. Alzheimer's disease (AD) is a severe neurological disorder characterized by progressive degeneration of the brain with limited and less effective therapeutic interventions. Researchers have attempted to identify potential treatment of AD from existing drug however, the success of drug repositioning strategy in AD remains uncertain. This article briefly discusses the importance and effectiveness of drug repositioning strategies, the major obstacles in the development of drugs for Alzheimer's disease (AD), approaches to address these challenges, and the role of machine learning in identifying early markers of AD for improved management.

PMID:40164279 | DOI:10.1016/j.neuroscience.2025.03.064

Bioimpacts. 2024 Jun 26;15:29952. doi: 10.34172/bi.29952. eCollection 2025.

ABSTRACT

INTRODUCTION: Drug repurposing as a low-cost, time-saving, and often less risky strategy has been attractive for the treatment of coronavirus disease 2019 (COVID-19) during the pandemic. This trial aimed to evaluate the effectiveness of dolutegravir, an HIV-1 integrase inhibitor, in admitted patients with moderate COVID-19.

METHODS: This study was a randomized, double-blind, placebo-controlled clinical trial assessing the efficacy of dolutegravir in adults admitted to a hospital in Ghaemshahr, Mazandaran Province, Iran. Patients aged 18-80 years with early symptoms of moderate COVID-19, which was confirmed based on reverse transcription polymerase chain reaction (RT-PCR) and/or chest computed tomography (CT) scan, were considered to be included in this study. Patients were randomly assigned in a 1:1 ratio to receive 50 mg dolutegravir plus the standard treatment regimen or the same value of placebo plus the standard treatment regimen, daily for 7 days. The standard treatment regimen was remdesivir 200 mg on day 1 followed by 100 mg for five days or until discharge. The primary endpoint was recovery 10 days after the beginning of the study.

RESULTS: Between August 22 and October 23, 2021, of 120 patients who were enrolled, 93 patients were randomly assigned to receive 50 mg dolutegravir (n=46) or the placebo regimen (n=47). No significant difference was observed between the two intervention groups based on the obtained results including frequency of respiratory modes during the first five days of admission, respiratory rate, and O2 saturation during six time periods.

CONCLUSION: The results showed that in adult patients admitted to the hospital with moderate COVID-19, treatment with dolutegravir was not associated with improvement in clinical recovery. Larger randomized trials are required to provide more robust evidence about the effectiveness of dolutegravir.

PMID:40161930 | PMC:PMC11954744 | DOI:10.34172/bi.29952

Front Oncol. 2025 Mar 14;15:1519355. doi: 10.3389/fonc.2025.1519355. eCollection 2025.

ABSTRACT

The research and development of new anti-cancer drugs face challenges such as high costs, lengthy development cycles, and limited data on side effects. In contrast, the clinical safety and side effects of traditional drugs have been well established through long-term use. The development or repurposing of traditional drugs with potential applications in cancer treatment offers an economical, feasible, and promising strategy for new drug development. This article reviews the novel applications of traditional drugs in tumor immunotherapy, discussing how they can enhance tumor treatment efficacy through functional repositioning, while also reducing development time and costs. Recent advancements in cancer immunotherapy have revolutionized treatment options, but resistance to ICIs remains a significant challenge. Drug repurposing has emerged as a promising strategy to identify novel agents that can enhance the efficacy of immunotherapies by overcoming ICI resistance. A study suggests that drug repositioning has the potential to modulate immune cell activity or alter the tumor microenvironment, thereby circumventing the resistance mechanisms associated with immune checkpoint blockade. This approach provides a rapid and cost-effective pathway for identifying therapeutic candidates that can be quickly transitioned into clinical trials. To improve the effectiveness of tumor immunotherapy, it is crucial to explore systematic methods for identifying repurposed drug candidates. Methods such as high-throughput screening, computational drug repositioning, and bioinformatic analysis have been employed to efficiently identify potential candidates for cancer treatment. Furthermore, leveraging databases related to immunotherapy and drug repurposing can provide valuable resources for drug discovery and facilitate the identification of promising compounds. It focuses on the latest advancements in the use of antidiabetic drugs, antihypertensive agents, weight-loss medications, antifungal agents, and antiviral drugs in tumor immunotherapy, examining their mechanisms of action, clinical application prospects, and associated challenges. In this context, our aim is to explore these strategies and highlight their potential for expanding the therapeutic options available for cancer immunotherapy, providing valuable references for cancer research and treatment.

PMID:40161377 | PMC:PMC11949826 | DOI:10.3389/fonc.2025.1519355

AIMS Microbiol. 2025 Feb 5;11(1):126-149. doi: 10.3934/microbiol.2025007. eCollection 2025.

ABSTRACT

BACKGROUND: Drug repositioning has emerged as a promising strategy for assessing its antimicrobial efficacy in treating infectious diseases.

METHODS: Seventy-five samples were collected and investigated for the presence of Pseudomonas aeruginosa. Antibiotic resistance, hemolytic activity, twitching motility, and biofilm formation were assessed. lasI and lasR genes were detected using conventional PCR. Minimum inhibitory concentrations of paroxetine, fluoxetine, and levofloxacin were determined by broth micro-dilution. The fractional inhibitory concentration index was calculated to assess the interaction between fluoxetine/levofloxacin and paroxetine/levofloxacin combinations. Half the MIC values of the drugs were selected for inhibitory effect assessment for virulence factors. Antibacterial and healing effects of fluoxetine were investigated on 30 male albino rats using a digital camera, bacterial count, and histological examination.

RESULTS: Our 25 P. aeruginosa isolates were highly drug-resistant. 80%, 92%, and 80% of isolates were positive for twitching motility, hemolysis, and biofilm formation, respectively. 92% of isolates were positive for lasI gene and 96% for lasR gene. MICs of fluoxetine and paroxetine ranged from 32 to 512 µg/mL and MICs of levofloxacin ranged from 1 to 256 µg/mL. A synergistic outcome was observed in both combinations. Biofilm formation, twitching motility, and hemolysis were inhibited by paroxetine and fluoxetine in the majority of isolates. Fluoxetine/levofloxacin and paroxetine/levofloxacin combinations inhibited twitching motility, hemolysis, and biofilm formation in all isolates. Enhanced wound healing was observed in rats treated with fluoxetine and levofloxacin, with the fluoxetine/levofloxacin combination group demonstrating the most significant wound-healing effect. Bacterial count decreased in rats treated with levofloxacin, fluoxetine, and the levofloxacin/fluoxetine combination. Histological examination revealed higher wound healing in the levofloxacin-treated group than the fluoxetine group, and the combination treatment group displayed the fastest rate of wound healing.

CONCLUSIONS: Paroxetine and fluoxetine showed considerable antibacterial inhibitory effects against multi-drug resistant P. aeruginosa isolates. Fluoxetine showed significant improvement in anti-inflammatory effects and wound healing. To the best of our knowledge, this is the first Egyptian study to investigate the repurposing of paroxetine and fluoxetine as antibacterial agents. Further studies are needed to investigate their applicability as antibacterial agents as single agents or in combination with other antibiotics.

PMID:40161243 | PMC:PMC11950684 | DOI:10.3934/microbiol.2025007

Biochem Biophys Res Commun. 2025 Mar 25;760:151701. doi: 10.1016/j.bbrc.2025.151701. Online ahead of print.

ABSTRACT

The histone deacetylase group of proteins, which includes the sirtuins, contributes to several cellular processes and is intimately involved in cancer development. Sirtuins type two (SIRT2) is a constituent of the human sirtuin family, which modulates a range of biological functions and is recognized as a potential biomarker for numerous cancers. The impact of SIRT2 knockout on tumorigenesis is debated and varies with the type of tumor; nonetheless, pharmacological inhibition of SIRT2 results exclusively in growth inhibition of diverse cancer cell lines. As a result, SIRT2 regulation is thought to be a viable protein for treating cancer. Herein, the DrugBank database, containing >14,000 drug molecules, was repurposed to find potential anticancer medications that have the capacity to inhibit the SIRT2 protein utilizing in-silico techniques. In light of the experimental findings, the capability of AutoDock Vina1.1.2 software to anticipate the docking scores and poses of the SIRT2 inhibitors was assessed. SirReal2, a potential SIRT2 inhibitor, was the controller for this study. Notably, drugs with docking scores less than SiReal2 were chosen and introduced to molecular dynamics (MD) simulations, accompanied by binding affinities estimations utilizing the MM-GBSA approach. Interestingly, MM-GBSA calculations demonstrated that five drugs, namely DB11526, DB11977, DB15133, DB04739, and DB04632, revealed potential affinities as SIRT2 inhibitors exhibiting ΔGbinding less than -50.0 kcal/mol. The post-MD analyses were inspected for DB11526, DB11977, DB15133, DB04739, and DB04632, indicating excellent steadiness of these drugs bound to SIRT2 protein throughout the 200 ns MD. The ADMET features were also examined and were acceptable. These findings suggested that more attention should be paid to DB11526, DB11977, DB15133, DB04739, and DB04632 as SIRT2 inhibitors utilizing in-vitro/in-vivo assays to treat cancer disease.

PMID:40158406 | DOI:10.1016/j.bbrc.2025.151701

Neurotherapeutics. 2025 Mar 28:e00576. doi: 10.1016/j.neurot.2025.e00576. Online ahead of print.

ABSTRACT

Glioblastoma (GB) is an incurable cancer of the brain, and there is an urgent need to identify effective treatments. This may be achieved by either identifying new molecules or through drug repurposing. To ascertain the therapeutic potential of known GSK-3β and/or PDE7 inhibitors in GB, a drug screening was conducted using a Drosophila melanogaster glioma model. VP3.15, a dual inhibitor with anti-inflammatory and neuroprotective roles in multiple sclerosis, was selected for further investigation. VP3.15 demonstrated robust anti-tumor efficacy against a panel of human and mouse GB cells; however, its capacity to inhibit orthotopic growth was only observed in a wild-type PTEN cell line. The in vivo dependence on PTEN was further suggested with the results in fly gliomas. The analysis of the VP3.15-treated tissues revealed a notable reduction in the number of myeloid cells and in the degree of vascularization. Mechanistic studies indicate that VP3.15 diminishes the production of GAL9, a key molecule that stimulates pro-angiogenic macrophages. Our findings substantiate the pro-tumoral function of GSK-3β, which might depend on the PTEN genetic status. Furthermore, we have delineated the therapeutic potential of VP3.15, which acts through the inhibition of the supportive role of the GB microenvironment. This molecule could be safely and effectively utilized after PTEN characterization in GB patients.

PMID:40157890 | DOI:10.1016/j.neurot.2025.e00576

Daru. 2025 Mar 29;33(1):17. doi: 10.1007/s40199-025-00560-3.

ABSTRACT

BACKGROUND: Mebendazole (MBZ) is an anthelmintic drug that was repurposed as an anti-cancer agent.

OBJECTIVES: This study aimed at formulating MBZ into stearylamine tailored spanlastics dispersed in nanogel for enhancing MBZ anti-tumor efficacy against skin cancer.

METHODS: MBZ spanlastics were prepared by thin film hydration using 21 × 31 factorial design. The formulation variables were the total amount (mg) of Span 60 and Tween 80 in the formulations and the ratio between Span 60 and Tween 80.

RESULTS: Optimal spanlastics formulation was composed of 400 mg of Span 60 and Tween 80 in a ratio of 2:1 and showed EE% of 78 ± 2.9% and PS of 284.00 ± 35.36 nm. Stearylamine (20 mg) was added to the optimized formulation and showed acceptable positive charge (zeta potential = 47.53 ± 1.50 mV). It was dispersed in 30% Tetronic®1107 solution to form a nanogel. MBZ nanogel was assessed for their cytotoxic effect on cell proliferation against human malignant melanoma and epidermoid carcinoma cell lines and showed 38.70 ± 1.70% and 48.60 ± 0.50% (respectively) cell proliferation compared to the control group (100%). Finally, its permeation through Wistar rat skin was tested.

CONCLUSION: SA-spanlastics nanogel holds potential as an effective nanocarrier for boosting MBZ anti-cancer efficacy.

PMID:40156679 | DOI:10.1007/s40199-025-00560-3

BioData Min. 2025 Mar 28;18(1):27. doi: 10.1186/s13040-025-00442-z.

ABSTRACT

The integration of multi-omics data from diverse high-throughput technologies has revolutionized drug discovery. While various network-based methods have been developed to integrate multi-omics data, systematic evaluation and comparison of these methods remain challenging. This review aims to analyze network-based approaches for multi-omics integration and evaluate their applications in drug discovery. We conducted a comprehensive review of literature (2015-2024) on network-based multi-omics integration methods in drug discovery, and categorized methods into four primary types: network propagation/diffusion, similarity-based approaches, graph neural networks, and network inference models. We also discussed the applications of the methods in three scenario of drug discovery, including drug target identification, drug response prediction, and drug repurposing, and finally evaluated the performance of the methods by highlighting their advantages and limitations in specific applications. While network-based multi-omics integration has shown promise in drug discovery, challenges remain in computational scalability, data integration, and biological interpretation. Future developments should focus on incorporating temporal and spatial dynamics, improving model interpretability, and establishing standardized evaluation frameworks.

PMID:40155979 | DOI:10.1186/s13040-025-00442-z

BMC Cancer. 2025 Mar 28;25(1):560. doi: 10.1186/s12885-025-13845-2.

ABSTRACT

BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, particularly due to advanced-stage metastasis. P-cadherin (CDH3), a potential therapeutic target, is highly expressed in CRC tissues and associated with poor prognosis and metastasis. However, the mechanisms underlying its role in CRC progression and its translational potential remain poorly understood.

MATERIALS AND METHODS: This study integrated multiple public databases (TCGA, HCMDB, UALCAN, HPA, UniProt, cBioPortal, and GEO) to evaluate CDH3 expression, construct a prognostic model, and perform functional and translational analyses. Immunohistochemistry was used to validate CDH3 protein expression in clinical samples. Additional analyses included correlations with clinicopathological parameters, immune infiltration (TIDE, TISIDB), functional enrichment (KEGG, GSEA), drug sensitivity (GSCA), and molecular docking (MOE). Single-cell sequencing (CancerSEA, HPA) was also conducted to explore CDH3's role at the single-cell level.

RESULTS: CDH3 expression was significantly elevated in CRC tissues and correlated with poor prognosis, recurrence, and metastasis. CDH3 expression was associated with the infiltration of resting immune cells, particularly dendritic cells, and enrichment analysis revealed its critical role in CRC metastasis through extracellular matrix (ECM) and local adhesion pathways. Notably, afatinib emerged as a promising candidate for targeting CDH3 via "drug repositioning," a process involving the repurposing of existing drugs for new therapeutic applications.

CONCLUSION: This study provides novel insights into CDH3's role in CRC metastasis and its potential as a therapeutic target. The translational potential of CDH3, including its integration with immunotherapy and drug repositioning strategies, offers a promising avenue for the treatment of metastatic CRC.

PMID:40155851 | DOI:10.1186/s12885-025-13845-2

Br J Pharmacol. 2025 Mar 28. doi: 10.1111/bph.70018. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Opioid use disorder (OUD) is a pressing public health concern marked by frequent relapse during periods of abstinence, perpetuated by negative affective states. Classical antidepressants or the currently prescribed opioid pharmacotherapies have limited efficacy to reverse the negative affect or prevent relapse.

EXPERIMENTAL APPROACH: Using mouse models, we investigated the effects of ketamine's metabolite (2R,6R)-hydroxynorketamine (HNK) on reversing conditioning to sub-effective doses of morphine in stress-susceptible mice, preventing conditioned-place aversion and alleviating acute somatic abstinence symptoms in opioid-dependent mice. Additionally, we evaluated its effects on anhedonia, anxiety-like behaviours and cognitive impairment during protracted opioid abstinence, while mechanistic studies examined cortical EEG oscillations and synaptic plasticity markers.

KEY RESULTS: (2R,6R)-HNK reversed conditioning to sub-effective doses of morphine in stress-susceptible mice and prevented conditioned-place aversion and acute somatic abstinence symptoms in opioid-dependent mice. In addition, (2R,6R)-HNK reversed anhedonia, anxiety-like behaviours and cognitive impairment emerging during protracted opioid abstinence plausibly via a restoration of impaired cortical high-frequency EEG oscillations, through a GluN2A-NMDA receptor-dependent mechanism. Notably, (2R,6R)-HNK facilitated the extinction of opioid conditioning, prevented stress-induced reinstatement of opioid-seeking behaviours and reduced the propensity for enhanced morphine self-consumption in mice previously exposed to opioids.

CONCLUSIONS AND IMPLICATIONS: These findings emphasize the therapeutic potential of (2R,6R)-HNK, which is currently in Phase II clinical trials, in addressing stress-related opioid responses. Reducing the time and cost required for development of new medications for the treatment of OUDs via drug repurposing is critical due to the opioid crisis we currently face.

PMID:40155780 | DOI:10.1111/bph.70018

Cancer Lett. 2025 Mar 26:217660. doi: 10.1016/j.canlet.2025.217660. Online ahead of print.

ABSTRACT

Medulloblastoma (MB) represents the most common malignant central nervous system tumor in childhood. The nervous system plays a critical role in the progression of MB, with interactions between the nervous system and cancer significantly influencing oncogenesis, tumor growth, invasion, stemness, and metabolism. These interactions also regulate angiogenesis, metastatic dissemination, the tumor immune microenvironment, and drug resistance. Investigating the nervous system-MB axis holds promise for identifying diagnostic markers, prognostic biomarkers, and therapeutic targets. It also provides insights into the molecular mechanisms underlying MB and informs the development of novel therapeutic strategies. This review summarizes the latest advancements in understanding the interplay between the nervous system and MB, including the role of glial cells in MB and the potential of drug repurposing targeting nervous system components for MB treatment. These findings underscore promising diagnostic and therapeutic opportunities for MB management. Additionally, we outline future research directions in neurosciences that may pave the way for innovative therapeutic approaches and deepen our understanding of this complex disease.

PMID:40154912 | DOI:10.1016/j.canlet.2025.217660

Ann Pharm Fr. 2025 Mar 26:S0003-4509(25)00047-1. doi: 10.1016/j.pharma.2025.03.005. Online ahead of print.

ABSTRACT

OBJECTIVES: The key objective of present research is to effectively treat lung cancer with repurposed celecoxib while overcoming challenges such as solubility, bioavailability, non-selectivity, and negative effects by delivering celecoxib through nanostructured lipid carriers via the parenteral route.

METHODS: Celecoxib-laden nanostructured lipid carriers were manufactured by melt-emulsification ultrasonication approach and optimized through Box-Behnken Design. The celecoxib nanostructured lipid carriers were examined for particle size, % entrapment efficiency, zeta potential, in vitro release, cytotoxicity, stability, etc. Results: The optimized celecoxib nanostructured lipid carriers displayed a % entrapment efficiency of 91.69±4.9% and particle size of 132.1±6.8 nm with a polydispersity index of 0.41±0.06, and a zeta potential of -39.1 ± 3.0 mV. Notably, celecoxib nanostructured lipid carriers exhibited better and controlled celecoxib release at phosphate buffer solution pH 6.8 than pH 7.4, revealing the tumor-targeting potential of nanostructured lipid carriers. Also, the release of celecoxib from nanostructured lipid carriers was controlled for 48 h, indicating reduced chances of systemic toxicity. The in vitro cytotoxicity against A549 cells of celecoxib nanostructured lipid carriers was 1.5-fold greater than that of pure celecoxib, confirming significant anti-lung cancer effectiveness. Further, the celecoxib-loaded nanostructured lipid carriers remained stable for twelve weeks at cold and ambient temperatures.

CONCLUSION: Thus, the given research concludes that parenteral administration of nanostructured lipid carriers could be a harmless, efficient, and novel choice to treat lung cancer using repurposed celecoxib.

PMID:40154777 | DOI:10.1016/j.pharma.2025.03.005

Cell Genom. 2025 Mar 21:100820. doi: 10.1016/j.xgen.2025.100820. Online ahead of print.

ABSTRACT

Most variants identified from genome-wide association studies (GWASs) are non-coding and regulate gene expression. However, many risk loci fail to colocalize with expression quantitative trait loci (eQTLs), potentially due to limited GWAS and eQTL analysis power or cellular heterogeneity. Population-scale single-cell RNA-sequencing (scRNA-seq) datasets are emerging, enabling mapping of eQTLs in different cell types (sc-eQTLs). Compared to eQTL data from bulk tissues (bk-eQTLs), sc-eQTL datasets are smaller. We propose a joint model of bk-eQTLs as a weighted sum of sc-eQTLs (JOBS) from constituent cell types to improve power. Applying JOBS to One1K1K and eQTLGen data, we identify 586% more eQTLs, matching the power of 4× the sample sizes of OneK1K. Integrating sc-eQTLs with GWAS data creates an atlas for 14 immune-mediated disorders, colocalizing 29.9% or 32.2% more loci than using sc-eQTL or bk-eQTL alone. Extending JOBS, we develop a drug-repurposing pipeline and identify novel drugs validated by real-world data.

PMID:40154479 | DOI:10.1016/j.xgen.2025.100820

J Infect Public Health. 2025 Mar 19;18(6):102763. doi: 10.1016/j.jiph.2025.102763. Online ahead of print.

ABSTRACT

BACKGROUND: Leprosy and tuberculosis caused by Mycobacterium leprae and Mycobacterium tuberculosis, respectively, are chronic infections with significant public health implications. While leprosy affects the skin and peripheral nerves and tuberculosis primarily targets the lungs, both diseases involve systemic immune responses. This study integrates transcriptomic analysis cheminformatics and molecular dynamics simulations to identify molecular mechanisms and potential therapeutic targets.

METHODS: Transcriptomic datasets were analyzed to identify dysregulated genes and pathways. Pathway enrichment tissue-specific and bulk RNA-seq expression analyses provided biological context. System biology networks revealed regulatory hub genes and molecular docking studies evaluated CHEMBL compounds as potential therapeutics. Molecular dynamics (MD) simulations assessed the stability of top ligand-protein complexes through RMSD RMSF and MM-GBSA free energy calculations.

RESULTS: Gene expression analysis identified 13 core dysregulated genes, including HSP90AA1 MAPK8IP3 and ZMPSTE24. Tissue-specific expression localized pivotal genes to lung tissues and immune cells with HSP90AA1 highly expressed in alveolar macrophages and epithelial cells. HSP90AA1 gene emerged as a central hub gene with 96 interactions involved in stress response pathways. Docking studies identified CHEMBL3653862 and CHEMBL3653884 with strong binding affinities (-10.16 to -12.69 kcal/mol) interacting with Asp93 and Tyr139. MD simulations confirmed binding stability with RMSD fluctuations within 2.1-3.5 Å and MM-GBSA energy values supporting ligand-protein stability.

CONCLUSION: This study identifies HSP90AA1 as a potential drug target in leprosy and tuberculosis. Findings support host-directed therapy approaches and highlight the importance of computational modeling in accelerating drug discovery. The study provides a foundation for future experimental validation, including in vitro and in vivo testing to advance drug repurposing strategies for these chronic infections.

PMID:40153981 | DOI:10.1016/j.jiph.2025.102763

Biomedicines. 2025 Mar 13;13(3):706. doi: 10.3390/biomedicines13030706.

ABSTRACT

After it has metastasized, bladder cancer, the malignant transformation of the bladder urothelium, continues to be a common cause of death after maximal use of all currently available standard treatments. To address this problem in 2025, the drug repurposing movement within oncology aims to identify medicines in common general medical care use that have data indicating that they can interfere or inhibit a growth driving element that has been identified in bladder cancer. This paper now outlines extensive preclinical data showing that four drugs from general medical practice meet these criteria-the melatonergic drug ramelteon, the antidepressant fluoxetine, the antibiotic dapsone, and the analgesic drug celecoxib. This is the UBC4 regimen, meant as a possible adjunct added to standard treatments of metastatic bladder cancer. Three factors justify a clinical pilot trial of UBC4: (1) the UBC4 drugs are usually well tolerated and carry a low risk of harm, (2) the commonly fatal outcome of bladder cancer once it has widely metastasized, plus (3) the strong preclinical database showing UBC growth inhibition by each of the individual UBC4 drugs as outlined in this paper.

PMID:40149682 | DOI:10.3390/biomedicines13030706

Antibiotics (Basel). 2025 Mar 18;14(3):315. doi: 10.3390/antibiotics14030315.

ABSTRACT

Background: Phosphoinositide 3-kinase is a potent target for cancer therapy due to its significant role in the regulation of cellular growth and proliferation. Dysregulation of the PI3k signaling cascade can constitutively activate growth pathways to trigger the progression of cancer, resulting in the development of multiple inhibitors as cancer therapeutics. Objectives: The wide array of cells expressing PI3k also include immune cells, and the inhibition of these receptors has shown promise in combating inflammation and infectious disease, a relationship we sought to examine further. Methods: We infected wild-type and PI3kγ knockout murine macrophages as well as PI3kγ inhibitor-treated THP-1 human macrophage-like cells with Staphylococcus aureus and quantified inflammation through gene expression analysis, protein secretion assays, and immunofluorescence imaging. Results: We observed that knockout of PI3kγ in murine macrophages alongside pharmacological inhibition through IPI549 treatment in THP-1 cells led to an NF-κB-driven suppression in transcription and release of inflammatory cytokines upon infection with methicillin-resistant Staphylococcus aureus. We were also able to confirm that this suppression of NF-κB translocation and subsequent decrease in inflammatory cytokine release did not compromise and even slightly boosted the bacterial killing ability. Conclusion: PI3k is primarily targeted for cancer therapies, but further exploration can also be carried out on its potential roles in treating bacterial infection.

PMID:40149125 | DOI:10.3390/antibiotics14030315

Antibiotics (Basel). 2025 Feb 25;14(3):231. doi: 10.3390/antibiotics14030231.

ABSTRACT

Background/Objectives:Streptococcus pneumoniae (S. pneumoniae) is a major pathogen causing severe infectious diseases, with an escalating issue of antimicrobial resistance that threatens the efficacy of existing antibiotics. Given the challenges in developing traditional antibiotics, drug repurposing strategies offer a novel approach to address the resistance crisis. This study aims to evaluate the antibacterial and anti-biofilm activities of the approved non-antibiotic anticancer drug carmofur against multidrug-resistant S. pneumoniae, and investigate the mechanism of action, and assess therapeutic potential in vivo. Methods/Results: Antimicrobial tests revealed that carmofur exhibited strong antibacterial activity against multidrug-resistant S. pneumoniae strains, with minimum inhibitory concentrations (MICs) ranging from 0.25 to 1 µg/mL. In the biofilm detection experiments, carmofur not only inhibited the formation of biofilms, but also effectively removed biofilms under high concentration conditions. Mechanistic studies showed that carmofur disrupted bacterial membrane permeability and decreased intracellular ATP levels. Molecular docking and dynamics simulation assays indicated that carmofur could stably bind to thymidylate synthase through hydrogen bonding and hydrophobic interactions, thereby exerting antibacterial effects. Meanwhile, carmofur was able to repress the expression of the thyA gene at the mRNA level. In a mouse infection model, the carmofur treatment group showed a reduction of approximately two log levels in bacterial load in lung tissue and blood, a significant decrease in the levels of inflammatory cytokines TNF-α and IL-6, and an improvement in survival rate to 60%. Conclusions: In summary, carmofur demonstrated significant antibacterial and anti-biofilm activities against multidrug-resistant S. pneumoniae and showed good anti-infective effects in vivo, suggesting its potential clinical application as a therapeutic agent against drug-resistant bacteria.

PMID:40149043 | DOI:10.3390/antibiotics14030231

Biol Direct. 2025 Mar 27;20(1):38. doi: 10.1186/s13062-025-00631-0.

ABSTRACT

BACKGROUND: Acute kidney injury (AKI) remains a critical condition with limited therapeutic options, predominantly managed by renal replacement therapy. The challenge of developing targeted treatments persists.

METHODS: We integrated genetic data related to druggable proteins and gene expression with AKI genome-wide association study (GWAS) findings. Based on multi-omics Mendelian randomization (MR), we identified the potential causal influence of 5,883 unique proteins and genes on AKI. We also performed using reverse MR and external cohort-based analysis to verify the robustness of this causal relationship. Expression patterns of these targets were examined using bulk transcriptome and single-cell transcriptome data. In addition, drug repurposing analyses were conducted to explore the potential of existing medications. We also constructed a molecular interaction network to explore the interplay between identified targets and known drugs.

RESULTS: Genetically predicted levels of seven proteins and twelve genes were associated with an increased risk of AKI. Of these, six targets (NCF1, TNFRSF1B, APEH, ACADSB, ADD1, and FAM3B) were prioritized based on robust evidence and validated in independent cohorts. Reverse MR showed a one-way causal relationship of targets. These targets are predominantly expressed in proximal tubular cells, endothelial cells, collecting duct-principal cells, and immune cells within both AKI-affected and normal tissues. Several promising drug repurposing opportunities were identified, such as telmisartan-NCF1, calcitriol-ACADSB, and ethinyl estradiol-ACADSB. The molecular interaction mapping and pathway integration analysis provided further insights, suggesting potential strategies for combinatorial therapies.

CONCLUSIONS: This extensive investigation identified several promising therapeutic targets for AKI and highlighted opportunities for drug repurposing. These findings offer valuable insights that could shape future research and the development of targeted treatments.

PMID:40148878 | DOI:10.1186/s13062-025-00631-0

Sci Rep. 2025 Mar 27;15(1):10606. doi: 10.1038/s41598-025-94283-9.

ABSTRACT

The 2019 pandemic of coronavirus disease (COVID-19) caused by SARS-CoV-2 led to millions of deaths worldwide since its emergence. The viral genomic material can code structural and non-structural proteins including the main protease or 3CLpro, a cysteine protease that cleavages the viral polyprotein generating 11 proteins that participate in viral pre-replication. Thus, 3CLpro is a promising therapeutic target for SARS-CoV-2 inhibition by new drugs or drug repositioning because 3CLpro is dissimilar to human proteases. We conducted in vitro assays demonstrating the modulation activity of ambenonium, a drug already used in Myasthenia gravis that acts by inhibiting the action of acetylcholinesterase, and had its potential inhibitory activity against viral replication pointed out in a previous in silico study. In concentrations of 100 µM, 50 µM, 25 µM, 10 µM, and 1 µM there was no inhibition in the formation of lysis plates, with a slight increase in the genome copy number at the higher concentrations evaluated. However, in the concentrations of 0,1 µM and 0,01 µM, there was a reduction in the number of lysis plates. This behavior suggests that the ambenonium acts as a modulator of viral activity in vitro. To investigate potential conformational changes in the protein between dimeric and monomeric forms in the presence of the compound, a local docking analysis was performed. Results indicated this conformational shift is possible, though further studies are needed to confirm these findings.

PMID:40148508 | DOI:10.1038/s41598-025-94283-9