Cancer Chemother Pharmacol. 2025 Aug 7;95(1):79. doi: 10.1007/s00280-025-04801-9.

ABSTRACT

PURPOSE: Oxaliplatin (L-OHP) is a platinum-based anticancer agent that induces peripheral neuropathy (OIPN), a dose-limiting toxicity caused by platinum accumulation in the dorsal root ganglion (DRG) and neuronal damage. Proton pump inhibitors (PPIs) have recently been proposed as preventive agents for OIPN; however, they have not been clinically implemented. This study aimed to evaluate the ameliorative effects of PPIs on OIPN using real-world data and a pharmacometrics approach based on animal data.

METHODS: Real-world database analysis was conducted using the Japanese Adverse Drug Event Report (JADER) database. We calculated the reporting odds ratios to evaluate the effects of the candidate drugs. Rats were intravenously administered L-OHP (5 mg/kg) once a week. Omeprazole (2-20 mg/kg) or esomeprazole (1-10 mg/kg) was orally administered on the five times a week. Blood and DRG samples were collected after L-OHP administration. The OIPN was assessed using the von Frey test. A pharmacokinetic-toxicodynamic (PK-TD) model analysis was performed using the obtained data.

RESULTS: The JADER analysis suggested that omeprazole may have a suppressive effect on OIPN. In animal study, co-administration of omeprazole or esomeprazole significantly decreased the platinum concentration in the DRG compared with L-OHP monotherapy and suppressed the development of OIPN in a dose-dependent manner. The PK-TD model of platinum composed of the DRG compartment quantitatively described the preventive effects of omeprazole and esomeprazole on OIPN.

CONCLUSION: Omeprazole and esomeprazole may be valuable agents for suppressing OIPN by inhibiting platinum influx into the DRG and exerting a potential neuroprotective effect.

PMID:40773063 | DOI:10.1007/s00280-025-04801-9

Sci Rep. 2025 Aug 6;15(1):28742. doi: 10.1038/s41598-025-14503-0.

ABSTRACT

Discovering new drug candidates for complex diseases like cancer is a significant challenge in modern drug discovery. Drug repurposing provides a cost-effective and time-efficient strategy to identify existing drugs for novel therapeutic targets. Here, we exploited an integrated in-silico approach to identify repurposed drugs that could inhibit programmed death-ligand 1 (PD-L1). PD-L1 is a crucial protein that plays a pivotal role in immune checkpoint regulation, making it a potential target for cancer treatment. Using a drug repurposing approach, we combined molecular docking and molecular dynamics (MD) simulations to study the binding efficiency of FDA-approved drug molecules targeting PD-L1. From the binding affinities and interaction analysis of the first screening, several molecules emerged as PD-L1 binders. Two of them, Lumacaftor and Vedaprofen, showed appropriate drug profiles and biological activities and stood out as highly potent binding partners of the PD-L1. MD simulation was performed for 500 ns to assess the conformational and stability changes of PD-L1-Lumacaftor and PD-L1-Vedaprofen complexes. The simulations revealed sustained structural integrity and stable binding of both complexes throughout the 500 ns trajectories, supporting their potential as PD-L1 inhibitors. While the findings are promising, they remain computational and require experimental validation to confirm biological efficacy and specificity. This study also emphasizes the role of bioinformatics approaches in drug repurposing that can help in the identification of novel anticancer agents.

PMID:40770405 | DOI:10.1038/s41598-025-14503-0

Microb Pathog. 2025 Aug 4:107949. doi: 10.1016/j.micpath.2025.107949. Online ahead of print.

ABSTRACT

Pulmonary tuberculosis (PTB) and gastroesophageal reflux disease (GERD) are clinically distinct but may share common molecular mechanisms. This study used integrative bioinformatics to identify 23 significantly dysregulated genes common to both conditions. Key regulatory microRNAs (hsa-miR-34a-5p, hsa-let-7b-5p, hsa-let-7g-5p) and macrophage-associated pathways were implicated. Interferon alpha/beta signaling emerged as a central shared pathway between PTB and GERD. Five hub genes (MYL9, OASL, ACTA2, DDX60L, and DDX60) were identified as common between these two conditions and their expressions were validated using quantitative real-time PCR. Drug repurposing analysis identified ribavirin as a promising candidate targeting the hub gene OASL, supported by a favorable binding affinity (-6.6 kcal/mol) and acceptable ADMET properties. These findings pave the way for understanding the molecular overlap between PTB and GERD and for developing targeted therapeutic strategies.

PMID:40769224 | DOI:10.1016/j.micpath.2025.107949

Front Pharmacol. 2025 Jul 22;16:1607814. doi: 10.3389/fphar.2025.1607814. eCollection 2025.

ABSTRACT

BACKGROUND: Oxaliplatin, in combination with 5-fluorouracil and leucovorin, is a standard treatment for colorectal cancer and shows high efficacy. However, oxaliplatin induces side effects, such as chemotherapy-induced peripheral neuropathy and myelosuppression, which may lead to dose reduction, temporary drug withdrawal, or discontinuation. Lecithinized superoxide dismutase (PC-SOD) is a drug delivery system formulation with improved blood stability and tissue affinity for SOD. A phase II clinical trial of PC-SOD for chemotherapy-induced peripheral neuropathy has been conducted, and its efficacy has been confirmed for certain parameters.

METHODS: In this study, we focused on myelosuppression, a major side effect of oxaliplatin, and aimed to elucidate the preventive effect of PC-SOD in a murine model of myelosuppression.

RESULTS: Oxaliplatin administration decreased the white blood cell, platelet, and red blood cell counts and hemoglobin levels in the whole blood of mice. PC-SOD treatment significantly restored the oxaliplatin-dependent reduction in white blood cell count (day 10). The gene expression of cytokines involved in hematopoietic progenitor cell differentiation and proliferation, including colony-stimulating factor (CSF)2, CSF3, interleukin (IL)-3, IL-4, IL-5, IL-6, IL-9, and stem cell factor, was also decreased by oxaliplatin administration. In contrast, PC-SOD treatment markedly restored the gene expression of these cytokines. In vivo imaging analysis showed that oxaliplatin treatment enhanced reactive oxygen species (ROS) production in the femur and tibia, whereas PC-SOD significantly suppressed this production. Furthermore, analysis of mouse-derived bone marrow cells revealed that PC-SOD suppressed oxaliplatin-induced cytotoxicity and ROS production in vitro.

CONCLUSION: These results suggest that PC-SOD exerts an antioxidant effect and prevents oxaliplatin-induced myelosuppression, particularly in a murine model of leukopenia.

PMID:40766760 | PMC:PMC12322972 | DOI:10.3389/fphar.2025.1607814

medRxiv [Preprint]. 2025 Jul 30:2025.07.29.25332397. doi: 10.1101/2025.07.29.25332397.

ABSTRACT

While antiretroviral therapy (ART) has significantly improved disease prognosis in people with HIV (PWH), understanding the biological mechanisms underlying plasma HIV-1 RNA viral load (VL) can inform additional strategies to slow HIV/AIDS disease progression. Here, we integrated multi-omic datasets and used two machine learning network biology tools (GRIN and MENTOR) to identify biological mechanisms associated with VL across 10 cohorts from multiple omics data sets. We integrated the following gene sets: 3 genes from HIV set point VL GWAS, 258 genes whose expression was associated with set point VL in CD4+ T-cells, 143 genes based on DNA methylation associations with VL, and 8 genes previously known to affect the pharmacokinetics of ART. Using GRIN, we retained 194 VL genes based on their high network interconnectivity. We then used MENTOR to collaboratively interpret subsets of these genes and identified the following biological processes: cell cycle checkpoint pathways associated with non-AIDS defining cancers, oxidative stress, viral replication, and interferon signaling. Using these network tools for multi-omic integration, we present a conceptual model of mechanisms underlying HIV VL, and identify drug repurposing candidates to complement existing ART to enhance treatment response and reduce HIV-related comorbidities.

PMID:40766151 | PMC:PMC12324665 | DOI:10.1101/2025.07.29.25332397

BioData Min. 2025 Aug 5;18(1):51. doi: 10.1186/s13040-025-00466-5.

ABSTRACT

Drug repurposing (DR) offers a promising alternative to the high cost and low success rate of traditional drug development, especially for complex diseases like Alzheimer's disease (AD). This study addressed DR for AD from three key angles: (1) demonstrating how disease-specific knowledge graphs can improve DR performance, (2) evaluating the role of large language models (LLMs) in enhancing the usability and efficiency of these graphs, and (3) assessing whether Graph-of-Thoughts (GoT)-enhanced LLMs, when integrated with AD knowledge graphs, can outperform traditional machine learning and LLM-based approaches. We tested five distinct DR strategies (DR1-DR5) for AD: DR1, a machine learning method using TxGNN; DR2, a machine learning model leveraging the Alzheimer's KnowledgeBase (AlzKB); DR3, an LLM-based chatbot built on AlzKB; DR4, our ESCARGOT framework combining GoT-enhanced LLMs with AlzKB; and DR5, a general reasoning-driven LLM approach. Results showed that AlzKB significantly improved DR outcomes. ESCARGOT further enhanced performance while reducing the need for coding or advanced expertise in knowledge graph analysis. Because the architecture of AlzKB is easily adaptable to other diseases and ESCARGOT can integrate with various knowledge graph platforms, this framework offers a broadly applicable, innovative tool for accelerating drug discovery through repurposing.

PMID:40764997 | DOI:10.1186/s13040-025-00466-5

BMC Pharmacol Toxicol. 2025 Aug 5;26(1):145. doi: 10.1186/s40360-025-00983-3.

ABSTRACT

OBJECTIVE: Prostate cancer remains a prevalent global health challenge, with limited treatment options for advanced stages. There is a critical need to identify effective therapies through systematic integration of genomic and biological data.

METHODS: We analyzed 10,911 single nucleotide polymorphisms (SNPs) in 554 genes from genome- and phenome-wide association studies to identify biological risk genes for prostate cancer. Bioinformatic analysis was used to map these genes to key pathways and potential drug targets. Drug repurposing opportunities were assessed through Connectivity Map (CMap) transcriptomic signature analysis in the PC3 prostate cancer cell line, with additional molecular docking studies to evaluate drug-target interactions.

RESULTS: We identified 77 prostate cancer-associated genes. Drug repurposing analysis revealed 59 drugs targeting 13 genes, including 11 approved for prostate cancer and 22 in clinical or preclinical development. Notably, 26 candidate drugs had not been previously linked to prostate cancer. CMap analysis prioritized five candidates: estradiol-benzoate and estradiol-cypionate (targeting ESR2), which showed the highest CMap scores, danazol and oxymetholone (targeting AR), and selumetinib (targeting MAP2K1/MEK), each demonstrating potential to modulate key pathways in prostate cancer. Molecular docking analysis further supported these findings, revealing that estradiol-benzoate and estradiol-cypionate have strong predicted binding affinities for ESR2, while selumetinib robustly interacts with MAP2K1. Conversely, danazol and oxymetholone displayed weaker predicted binding, suggesting a more limited capacity for direct protein engagement.

CONCLUSIONS: Integrating genomics, bioinformatics, and molecular docking provides an effective strategy for identifying and prioritizing drug repurposing candidates in prostate cancer. Estradiol-benzoate, estradiol-cypionate, and selumetinib emerge as promising candidates, meriting further preclinical and clinical evaluation for advanced prostate cancer therapy.

PMID:40764606 | DOI:10.1186/s40360-025-00983-3

Sci Rep. 2025 Aug 5;15(1):28531. doi: 10.1038/s41598-025-13845-z.

ABSTRACT

KDM5B, a lysine-specific histone demethylase, is widely upregulated in breast cancer. The current study investigated the role of KDM5B in breast cancer and explored the repurposing potential of the antiviral drug abacavir (ABC). The cytotoxic effects and the effect of ABC sensitization on doxorubicin (DOX) efficacy were evaluated using 2-D and 3-D cell culture models. KDM5B expression was elevated in breast cancer tissues compared to normal breast tissues. In vitro studies demonstrated that ABC treatment reduced KDM5B expression in breast cancer cells and increased their sensitivity towards DOX. ABC induced late apoptosis and S-phase arrest, while the ABC + DOX combination led to S/G2 phase arrest, late apoptosis, and cell death. Data generated from patient-derived breast tumoroids corroborated the 2-D cell culture-based findings. Additionally, molecular docking studies indicated that the active drug metabolite carbovir triphosphate (CBV-TP) could interact with the DNA polymerase β-DNA complex, suggesting its potential mechanism to be incorporated into the DNA synthesis cycle, leading to cell cycle arrest in tumor cells. Our findings highlight the repurposing potential of ABC to target KDM5B in breast cancer. This approach enhanced the efficacy of DOX, which could allow further dose reduction and reduced side effects, offering a promising therapeutic strategy.

PMID:40764352 | DOI:10.1038/s41598-025-13845-z

J Exp Clin Cancer Res. 2025 Aug 4;44(1):225. doi: 10.1186/s13046-025-03478-5.

ABSTRACT

BACKGROUND: The metastatic microenvironment is often rich in tumor-associated macrophages (TAMs). In uveal melanoma (UM), high levels of TAMs positively correlate with tumor progression and poorer prognosis. We hypothesize that the immunomodulation of TAMs can remodel the UM tumor microenvironment and make it more susceptible to therapeutic interventions.

METHODS: In our work, we designed a novel computational pipeline that combines single-cell transcriptomics data, network analysis, multicriteria decision techniques, and pharmacophore-based docking simulations to select molecular targets and matching repurposable drugs for TAM immunomodulation. The method generates a ranking of drug-target interactions, the most promising of which are channeled towards experimental validation.

RESULTS: To identify potential immunomodulatory targets, we created a network-based representation of the TAM interactome and extracted a regulatory core conditioned on UM expression data. Further, we selected 13 genes from this core (NLRP3, HMOX1, CASP1, GSTP1, NAMPT, HSP90AA1, B2M, ISG15, LTA4H, PTGS2, CXCL2, PLAUR, ZFP36, TANK) for pharmacophore-based virtual screening of FDA-approved compounds, followed by flexible molecular docking. Based on the ranked docking results, we chose the interaction between caspase-1 and clindamycin for experimental validation. Functional studies on macrophages confirmed that clindamycin inhibits caspase-1 activity and thereby inflammasome activation, leading to a decrease in IL-1β, IL-18, and gasdermin D cleavage products as well as a reduction in pyroptotic cell death. This clindamycin-mediated inhibition of caspase-1 was also observable in TAMs derived from the bone marrow of multiple myeloma patients.

CONCLUSIONS: Our computational workflow for drug repurposing identified clindamycin as an efficacious inhibitor of caspase-1 that suppresses inflammasome activity and pyroptosis in vitro in TAMs.

PMID:40759978 | DOI:10.1186/s13046-025-03478-5

Biochem Biophys Rep. 2025 Jul 25;43:102175. doi: 10.1016/j.bbrep.2025.102175. eCollection 2025 Sep.

ABSTRACT

Candida glabrata is well known to be the second most common cause of invasive candidiasis (IC) within immunocompromised and hospitalized patients, after Candida albicans. Candida species adhere to host cells and implanted medical devices by means of cell wall proteins (CWP), of which the moonlight proteins have recently been described and are of particular importance because they have been identified in response to various virulence and/or pathogenic factors. Among the identified CWP moonlights, fructose-bisphosphate aldolase (Fba1) and pyruvate kinase (Pk) have been observed to confer immune protection against C. albicans and C. glabrata in a mouse model. In other pathogens, these proteins have been used as therapeutic targets. As the treatment of IC has been based on four main drug classes for decades, the Candida species has developed resistance mechanisms. In addition, C. glabrata has an innate resistance to the antifungal drugs, which makes the treatment of IC by this pathogen difficult. It is essential to have new formulations that allow new treatments of patients affected by this pathogen, so new targets with antifungal activity is of primary necessity. For this purpose, in this study we propose the moonlight CWPs Fba1 and Pk as novel candidates for drug targets. Using structural modeling, virtual database analysis, in vitro susceptibility tests, and enzymatic activity assays, we propose the use of new chemical molecules as potential antifungals against C. glabrata. In this sense, we chose to evaluate three chemical molecules (FE1, FE2 and FE3), whose chemical structure gives them the possible molecular leadership against Fba1 and Pk. Through the susceptibility experiments, our data showed that of the three molecules evaluated, FE1 was the best ligand against C. glabrata. We also found that Fba1 and Pk of C. glabrata had the characteristics of therapeutic targets against IC. In the present work, considering a group of tools in silico and experiments in vitro it was possible to identify the best candidate molecule as a possible antifungal for the treatment of IC caused by C. glabrata.

PMID:40756780 | PMC:PMC12318263 | DOI:10.1016/j.bbrep.2025.102175

Theranostics. 2025 Jun 23;15(15):7653-7676. doi: 10.7150/thno.112608. eCollection 2025.

ABSTRACT

Background: The complexity of biological systems and misconceptions about neuroprotection have hindered the development of neuroprotective drugs for ischemic stroke. This study aims to identify new neuroprotective agents by integrating ischemic stroke transcriptomics with neuronal protection data using a Multidimensional Data-Driven Computational Drug Repositioning strategy (MDCDR). Methods: Three microarray datasets related to ischemic stroke (GSE16561, GSE58294, and GSE22255) were obtained from the GEO dataset and pre - processed to analyze differentially expressed genes (DEGs). The Connectivity Map (CMap) database was used to predict potential drugs. A neuroprotection activity prediction model was constructed by combining six molecular fingerprints with three machine learning algorithms (Random Forest RF, Support Vector Machine SVM, Gradient Boosting Decision Tree GBDT) to screen for potential neuroprotective agents. The efficacy of the screened compounds was evaluated through in vitro experiments on SH-SY5Y cells treated with oxygen-glucose deprivation/reperfusion (OGD/R) and in vivo experiments on middle cerebral artery occlusion/reperfusion (MCAO/R) rat models. Multiple experimental techniques (such as RNA sequencing, DARTS, CETSA, etc.) were used to explore their potential mechanisms of action. Results: The MDCDR strategy screened out 19 potential neuroprotective agents, among which sulbutiamine (SUL) stood out. SUL significantly increased the survival rate, reduced neurological deficit scores, and decreased neuronal loss in MCAO/R rat models, and inhibited cell death in OGD/R - induced cell models. Mechanistic studies revealed that SUL inhibited pyruvate dehydrogenase kinase 2 (PDK2), enhanced mitochondrial function, reduced reactive oxygen species (ROS) levels, thereby suppressing the MAPK signaling pathway and reducing neuronal apoptosis. Silencing PDK2 abolished the protective effect of SUL on OGD/R - treated SH - SY5Y cells. Conclusion: This study successfully developed the MDCDR strategy for screening neuroprotective agents for ischemic stroke. SUL was identified as a promising neuroprotective agent, and PDK2 was a crucial target. This research provides new directions and a theoretical basis for the development of neuroprotective agents against ischemic stroke.

PMID:40756350 | PMC:PMC12316036 | DOI:10.7150/thno.112608

Curr Top Med Chem. 2025 Jul 30. doi: 10.2174/0115680266382257250721051440. Online ahead of print.

ABSTRACT

Precision medicine's quick development has transformed the way cancer is treated, and because small-molecule kinase inhibitors can specifically block the abnormal signaling pathways that cause tumor growth and progression, they are now a key component of targeted therapy. This review explores the most recent advancements in kinase inhibitor design and optimization, with a focus on novel drug scaffolds, improved structure-activity relationships (SARs), and molecular modification techniques meant to improve target selectivity, potency, and pharmacokinetic profiles. Emerging strategies to combat resistance mechanisms are heavily emphasized, such as the use of dual-target inhibitors that block parallel signaling cascades, allosteric modulators that bind to non-ATP sites, and combination therapies that work in concert to increase efficacy while reducing resistance. A thorough summary of the kinase inhibitors that are now FDA-approved for use in treating different forms of cancer is also included in the review, along with information on their safety profiles, clinical effectiveness, and changing indications of usage. Additionally, it examines encouraging results from preclinical research and ongoing clinical studies assessing nextgeneration kinase inhibitors, which have the potential to further customize cancer treatment. In order to improve patient outcomes, address therapeutic resistance, and broaden the therapeutic scope of kinase-targeted interventions in oncology, the review concludes by highlighting future research directions, such as drug repurposing, computational drug discovery, and advanced precision oncology approaches.

PMID:40754874 | DOI:10.2174/0115680266382257250721051440

Bioorg Chem. 2025 Jul 30;164:108797. doi: 10.1016/j.bioorg.2025.108797. Online ahead of print.

ABSTRACT

The rising prevalence of antifungal resistance in Candida species poses a significant challenge to public health, necessitating the exploration of novel therapeutic strategies. This review highlights advancements in molecular innovations targeting Candida infections, emphasizing novel drug discovery approaches, including high-throughput screening, structure-based drug design, and synthetic modifications of existing molecules. We discuss emerging drug candidates in preclinical and clinical development, targeting key fungal pathways such as ergosterol biosynthesis, β-(1,3)-D-glucan synthesis, and novel metabolic regulators. Furthermore, drug repurposing strategies, leveraging known pharmacokinetics and pharmacodynamics of existing drugs, provide accelerated routes to new antifungal treatments. Collaborative efforts integrating pharmaceutical research, clinical insights, and technological advancements are imperative for the development of next-generation antifungal therapeutics. This review underscores the need for an interdisciplinary approach to antifungal drug discovery, ensuring effective and sustainable treatment options against resistant Candida strains.

PMID:40753878 | DOI:10.1016/j.bioorg.2025.108797

Semin Nephrol. 2025 Aug 1:151650. doi: 10.1016/j.semnephrol.2025.151650. Online ahead of print.

ABSTRACT

Advances in genomic diagnostics have enabled earlier and more precise identification of genetic kidney disease, but the translation of these insights into trial methodology and therapeutic development has lagged. This review examines the current challenges in nephrology trials-including disease heterogeneity, slow progression, and limited industry engagement-and explores how genomic information can address these barriers. Examples from trials in autosomal dominant polycystic kidney disease and other genetic kidney diseases demonstrate the feasibility and value of genomics-informed approaches, including genotype-based recruitment, post hoc genetic stratification, and drug repurposing. The emergence of genotype stratification, artificial intelligence tools, and gene-based therapies presents further opportunities to refine trial design and personalize treatment. However, incorporating genomics into clinical research also raises complex ethical and regulatory issues, including consent processes, data governance, and equitable access to testing and trial participation. As genomic testing becomes embedded in standard clinical practice, its alignment with clinical research infrastructure offers the potential to create a learning health system in nephrology. Realizing this potential will require cross-disciplinary coordination, international collaboration, and co-design with patients and communities. Integrating genetic nephrology into clinical trial conduct is not only feasible but essential to advancing precision medicine and improving outcomes for patients with kidney disease.

PMID:40752992 | DOI:10.1016/j.semnephrol.2025.151650

Connect Tissue Res. 2025 Aug 2:1-9. doi: 10.1080/03008207.2025.2538562. Online ahead of print.

ABSTRACT

Osteoarthritis (OA) is a leading cause of disability worldwide, significantly impacting patient mobility and quality of life. Its increasing prevalence presents a growing socioeconomic burden. Despite extensive research, no FDA-approved disease-modifying osteoarthritis drugs (DMOADs) exist, leaving patients reliant on symptomatic treatments like NSAIDs, corticosteroids, and joint replacement surgeries. A major challenge in OA drug development is the heterogeneity of the disease. Traditional approaches that target single molecular pathways often fail to address the multifactorial nature of OA. Given the high failure rate and costs of novel drug development, drug repurposing has emerged as a promising alternative. Several repurposed drugs, predominantly those affecting inflammation (e.g. Methotrexate, Adalimumab), metabolism (e.g. Metformin, Liraglutide) and bone homeostasis (e.g. Risedronate, Clodronate) have been investigated for OA. However, inconsistent clinical trial results underscore the need for improved screening, patient stratification, and mechanistic understanding. Recent insights into OA pathophysiology, such as the role of cellular senescence, mitochondrial dysfunction, and translational alterations, highlight novel targets for repurposing efforts. The future of OA drug repurposing will likely be shaped by advancements in high-throughput screening, artificial intelligence-driven drug discovery, and strategies that align treatments with patient-specific disease mechanisms. By integrating these innovations, drug repurposing holds potential to deliver DMOADs and improve patient outcomes worldwide.

PMID:40751563 | DOI:10.1080/03008207.2025.2538562

Sci Rep. 2025 Aug 1;15(1):28071. doi: 10.1038/s41598-025-13584-1.

ABSTRACT

Melanoma is still one of the most aggressive cancers, with global incidence and mortality rates expected to rise significantly by 2040. Surgical excision with adequate safety margins remains the standard treatment for primary cutaneous melanoma. However, the therapeutic approach to treat advanced stages or disease recurrence in melanoma is still challenging. Although initial responses to combined targeted therapies and immune checkpoint inhibitors often achieve clinical success, disease progression remains difficult to manage. Thus, there is an urgent need for novel and unexplored therapeutic strategies. Pirfenidone (PFD) is an antifibrotic drug approved for Idiopathic Pulmonary Fibrosis, with anti-inflammatory, and anti-oxidant properties. Its primary mechanism involves Transforming Growth Factorβ signalling downregulation, alongside with the suppression of cytokine and reactive oxygen species (ROS) release. Recently, it has been suggested that PFD may function as furin convertase enzyme inhibitor. Furin is involved in many physiological and pathological processes such as BRAF oncogene activation. In this study, we investigated the mechanisms of antitumoral effect of PFD in BRAF mutated human melanoma cell lines. Docking analysis revealed a close interaction between PFD and furin convertase active site. In vitro studies revealed that PFD reduced cell proliferation, clonogenicity, and invasiveness. Interestingly, the early antioxidant effect observed during PFD treatment was later replaced by a marked increase in ROS levels, along with p21 upregulation and induction of apoptosis. This multi-angle approach highlights a key role of furin in melanoma cell aggressiveness. Although, the present study lacks clinical data from melanoma patients, our observations suggest that PFD may represent a treatment option for metastatic melanoma cases that are resistant to conventional therapeutic interventions, through a drug repurposing approach.

PMID:40751072 | DOI:10.1038/s41598-025-13584-1

BMC Microbiol. 2025 Aug 1;25(1):472. doi: 10.1186/s12866-025-04163-5.

ABSTRACT

BACKGROUND: The emergence of multidrug-resistant (MDR) Staphylococcus aureus (S. aureus) seriously poses a serious threat to human health and presents a significant clinical challenge. Therefore, it is urgent to explore alternative treatments and develop novel antimicrobial agents. To investigate the antibacterial activity of Etalocib against S. aureus and elucidate its underlying mechanism of action.

RESULTS: Etalocib, a drug previously investigated in clinical trials, exhibited notable antibacterial activity against S. aureus, with a minimum inhibitory concentration (MIC) of ≤ 25 μM. Time-kill curves demonstrated concentration-dependent bactericidal effects. Etalocib could significantly inhibited biofilm formation and kill bacteria within mature biofilms. Moreover, permeability assays revealed that Etalocib treatment caused bacterial membrane damage, accompanied by dissipation of membrane potential. Checkerboard analysis showed that bacterial membrane phospholipids, including phosphatidylglycerol and cardiolipin, could neutralize the antibacterial activity of Etalocib in a dose-dependent manner. These findings suggest that the primary mechanism of action involves disruption of the bacterial membrane, potentially through interactions with membrane phospholipids, alterations in protein homeostasis, and disturbances in energy and metabolic processes. Notably, Etalocib significantly improved the survival rate of the Galleria mellonella in the methicillin-resistant S. aureus (MRSA) infection model.

CONCLUSIONS: The findings highlight the potential of Etalocib as an effective antibacterial agent for combating MDR S. aureus infections. It holds significant promise as a novel therapeutic option for the treatment of severe infections caused by Gram-positive pathogens.

PMID:40750851 | DOI:10.1186/s12866-025-04163-5

BMC Bioinformatics. 2025 Aug 1;26(1):203. doi: 10.1186/s12859-025-06237-7.

NO ABSTRACT

PMID:40750838 | DOI:10.1186/s12859-025-06237-7

Eur J Pharmacol. 2025 Jul 30:178007. doi: 10.1016/j.ejphar.2025.178007. Online ahead of print.

ABSTRACT

The cognitive decline associated with ageing is the most critical health issue affecting elderly individuals, and there is still a lack of effective interventions available. This study was designed to identify a drug capable of ameliorating age-related cognitive decline and the underlying mechanisms. Utilizing data mining of multisource databases and drug repositioning approaches based on transcriptome similarity, the cardiovascular drug ranolazine (Ran), was identified as a potential candidate with similar effects to those of resveratrol (RSV). Network pharmacology analysis predicted that Ran's effects on cognitive decline through the PI3K/AKT/mTOR signalling pathway. These predictions were subsequently verified using a combination of molecular, cellular, and tissue experiments, animal models of ageing induced by D-galactose, and omics studies. The results revealed that Ran extended the lifespan of Caenorhabditis elegans (C. elegans), improved the head swinging ability of ageing C. elegans, and alleviated mitochondrial membrane potential (MMP) damage in ageing hippocampal neuronal cells (HT22). In ageing rats, Ran not only enhanced spatial memory,exploratory behaviors and motor ability,but also alleviated mitochondrial structural damage in hippocampus and medial prefrontal cortex (mPFC). Notably, Ran alleviated age-related cognitive decline by regulating mitochondrial autophagy in hippocampus and mPFC through the PI3K/AKT/mTOR signalling pathway, rather its conventional mechanism of regulating fatty acid metabolism. In summary, this study reveals Ran's previously unrecognized role in alleviating age-related cognitive decline for the first time. These findings provide new options for the treatment of age-related cognitive decline and broaden the potential clinical applications of Ran.

PMID:40749868 | DOI:10.1016/j.ejphar.2025.178007

Schizophr Res. 2025 Jul 31;284:67-76. doi: 10.1016/j.schres.2025.07.022. Online ahead of print.

ABSTRACT

BACKGROUND: The reduced life expectancy observed in individuals with schizophrenia (SCZ) underscores the urgent need for novel therapeutic targets. Emerging evidence suggests that astrocytic dysfunction and immune-inflammatory processes contribute to SCZ pathophysiology. Low-dose methotrexate (MTX), an established immunomodulatory drug used for non-neurological conditions, demonstrated antipsychotic potential in early SCZ. However, the underlying mechanisms remain unknown.

AIMS: This study aimed to identify molecular targets of MTX within SCZ-relevant pathways, focusing on astrocytic and neuroimmune networks using in silico bioinformatics analysis and a rodent model for SCZ.

METHODS: In silico analysis: A bioinformatics-based approach was employed, integrating cognitive computing-generated knowledge graphs, modular co-expression analysis, and gene-drug interaction databases with a machine learning-based text-mining tool. Rodent model: The NMDA receptor antagonist MK-801-induced mouse model for SCZ was used to assess MTX's therapeutic potential, compared to clozapine. Behavioural outcomes (sociability and cognition) and astrocytic reactivity (GFAP expression in the medial prefrontal cortex, mPFC) were evaluated.

RESULTS: In silico: MTX preferentially targeted hub genes within astrocyte and NFκB modules. In astrocytes, MTX modulated NT5E, a key regulator of adenosine metabolism. In the NFκB module, MTX interacted with IL-6 and STAT3, both involved in immune regulation. Rodent model: MK-801 administration impaired sociability and cognition, accompanied by increased GFAP-positive astrocytes in the prelimbic mPFC, both of which were prevented by MTX. The neuroimmunomodulator effect of MTX was comparable to clozapine in both the in silico and rodent model.

CONCLUSION: Our findings provide mechanistic insights into the potential antipsychotic-like effects of low-dose MTX in SCZ, involving astrocytic modulation and immune regulation. Further experimental medicine studies in clinical populations stratified by astrocytic and neuroinflammatory biomarkers are warranted to validate these findings.

PMID:40749304 | DOI:10.1016/j.schres.2025.07.022