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

Psychol Med. 2025 May 22;55:e158. doi: 10.1017/S0033291725001096.

ABSTRACT

BACKGROUND: Precise stratification of patients into homogeneous disease subgroups could address the heterogeneity of phenotypes and enhance understanding of the pathophysiology underlying specific subtypes. Existing literature on subtyping patients with major depressive disorder (MDD) mainly utilized clinical features only. Genomic and imaging data may improve subtyping, but advanced methods are required due to the high dimensionality of features.

METHODS: We propose a novel disease subtyping framework for MDD by integrating brain structural features, genotype-predicted expression levels in brain tissues, and clinical features. Using a multi-view biclustering approach, we classify patients into clinically and biologically homogeneous subgroups. Additionally, we propose approaches to identify causally relevant genes for clustering.

RESULTS: We verified the reliability of the subtyping model by internal and external validation. High prediction strengths (PS) (average PS: 0.896, minimum: 0.854), a measure of generalizability of the derived clusters in independent datasets, support the validity of our approach. External validation using patient outcome variables (treatment response and hospitalization risks) confirmed the clinical relevance of the identified subgroups. Furthermore, subtype-defining genes overlapped with known susceptibility genes for MDD and were involved in relevant biological pathways. In addition, drug repositioning analysis based on these genes prioritized promising candidates for subtype-specific treatments.

CONCLUSIONS: Our approach successfully stratified MDD patients into subgroups with distinct clinical prognoses. The identification of biologically and clinically meaningful subtypes may enable more personalized treatment strategies. This study also provides a framework for disease subtyping that can be extended to other complex disorders.

PMID:40400388 | DOI:10.1017/S0033291725001096

J Biomed Sci. 2025 May 21;32(1):50. doi: 10.1186/s12929-025-01137-7.

ABSTRACT

BACKGROUND: Type 2 diabetes is an increasingly prevalent metabolic disorder with moderate to high heritability. Glycemic indices are crucial for diagnosing and monitoring the disease. Previous genome-wide association study (GWAS) have identified several risk loci associated with type 2 diabetes, but data from the Taiwanese population remain relatively sparse and primarily focus on type 2 diabetes status rather than glycemic trait levels.

METHODS: We conducted a comprehensive genome-wide meta-analysis to explore the genetics of glycemic traits. The study incorporated a community-based cohort of 145,468 individuals and a hospital-based cohort of 35,395 individuals. The study integrated genetics, transcriptomics, biological pathway analyses, polygenic risk score calculation, and drug repurposing for type 2 diabetes.

RESULTS: This study assessed hemoglobin A1c and fasting glucose levels, validating known loci (FN3K, SPC25, MTNR1B, and FOXA2) and discovering new genes, including MAEA and PRC1. Additionally, we found that diabetes, blood lipids, and liver- and kidney-related traits share genetic foundations with glycemic traits. A higher PRS was associated with an increased risk of type 2 diabetes. Finally, eight repurposed drugs were identified with evidence to regulate blood glucose levels, offering new avenues for the management and treatment of type 2 diabetes.

CONCLUSIONS: This research illuminates the unique genetic landscape of glucose regulation in Taiwanese Han population, providing valuable insights to guide future treatment strategies for type 2 diabetes.

PMID:40399988 | DOI:10.1186/s12929-025-01137-7

Sci Rep. 2025 May 21;15(1):17704. doi: 10.1038/s41598-025-00547-9.

ABSTRACT

This study explores the efficacy of glibenclamide, a KATP channel inhibitor, for treating Cantú syndrome (CS), a genetic disorder characterized by hypertrichosis and cardiovascular abnormalities. Treatment with glibenclamide for Cantú syndrome has only been reported in a single case report. In this study, we tested this repurposed drug in both a zebrafish model and an open-label trial with CS patients. CS zebrafish embryos, created using CRISPR/Cas9, were treated with glibenclamide. Their cardiac function was assessed using high-speed imaging. In the trial part of the study, four adults with CS used 2.5 mg glibenclamide daily for 8 months. Hypertrichosis, cardiac function, and edema were evaluated and glucose levels were monitored continuously. In the zebrafish model of CS glibenclamide reversed cardiac abnormalities. However, in the clinical trial, the effects on hypertrichosis were mixed, and there were no significant changes in cardiac phenotype or leg edema. One participant reported reduced facial erythema and puffiness, which relapsed post-trial. The treatment was generally safe, with multiple instances of level 1 hypoglycemia but no severe adverse events. In conclusion, glibenclamide can reverse cardiac abnormalities in a CS zebrafish model. Its effect on hypertrichosis and cardiovascular features in humans with CS are unclear and dosage increases are challenging due to hypoglycemia, which is important knowledge for treatment considerations in this rare genetic syndrome.Trial registration: EudraCT Number 2019-004651-36. Date of first registration 21/05/2021.

PMID:40399303 | DOI:10.1038/s41598-025-00547-9

Nutr Res Rev. 2025 May 21:1-54. doi: 10.1017/S0954422425100061. Online ahead of print.

ABSTRACT

To achieve infectivity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the virus responsible for COVID-19, must first traverse the upper respiratory tract mucosal barrier. Once infection is established, the cascading complexities of the pathophysiology of COVID-19 makes intervention extremely difficult. Thus, enhancing the defensive properties of the mucosal linings of the upper respiratory tract may reduce infection by SARS-CoV2 and indeed by other viruses such as influenza, which have been responsible for the two major pandemics of the last century. In this review we summarise potential opportunities for foods and nutrients to promote an adequate mucosal immune preparedness with an aim to assist protection against infection by SARS-CoV-2; to maximise the mucosal vaccination (IgA inducing) response to existing systemic vaccines; and to play a role as adjuvants to intranasal vaccines. We identify opportunities for vitamins A, and D, zinc, probiotics, bovine colostrum and resistant starch to promote mucosal immunity and enhance the mucosal response to systemic vaccines, and for vitamin A to also improve the mucosal response to intranasal vaccination. It is possible that an entirely different virus may in the future, by way of convergent evolution, utilise a similar upper respiratory tract infection pathway. A greater research focus on mucosal lymphoid immune protection in partnership with nutrition would result in greater preparedness for such an event.

PMID:40396597 | DOI:10.1017/S0954422425100061

Brain Commun. 2025 May 9;7(3):fcaf184. doi: 10.1093/braincomms/fcaf184. eCollection 2025.

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative condition for which novel disease modifying therapies are urgently needed. Given the increasing bottlenecks in drug discovery pipelines, repurposing existing drugs for ALS may represent a path to expedite translation and improve disease outcomes. However, ALS is a heterogeneous disease for which the aetiology remains poorly characterized, complicating efforts to effectively repurpose drugs. We propose that the polygenic architecture of ALS genetic liability, which ranges from ultra-rare, high-impact variation to common frequency loci of small-individual effect, could be leveraged to prioritize drug repurposing candidates which are more generalizable to the ALS clinical population. Here, we utilize common and rare frequency ALS genetic risk with a novel approach to uncover therapeutic classes that may be prospective repurposing opportunities in ALS. The common variant-led analyses integrated both positional-based and functional gene-based tests on SNP-genotype data from a genome-wide association study of ALS and implicated mitogen-activated protein kinase signalling related downregulation through B-Raf inhibitors as a prospective target for repurposing. The rare variant-led approaches leveraged rare variant burden testing of exonic variation on whole genome-sequencing data from a subset of the common variant genome-wide association study cohort and prioritized B-vitamin related candidates, such as cobalamin and niacin. Clinical characterization of these putative repurposing opportunities revealed genetic support to existing biology for which related compounds are actively proceeding through ALS clinical studies. Moreover, leveraging transcriptomic data from ALS derived cell lines carrying a selection of pathogenic variants in genes that cause familial forms of ALS (C9orf72, SOD1, FUS and TARDBP) suggested that the action of B-Raf inhibitors may be of particular relevance to C9orf72 carriers, whilst the signal for B-vitamin signalling related targets was strongest in SOD1 carriers. In summary, we demonstrate the importance of considering the therapeutic actionability of both common and rare-variant mediated risk for ALS given the immense biological heterogeneity of this disorder. Future pre-clinical and clinical studies are now warranted to further characterize the tractability of these prioritized compounds.

PMID:40395632 | PMC:PMC12089939 | DOI:10.1093/braincomms/fcaf184

Int J Biol Macromol. 2025 May 18:144106. doi: 10.1016/j.ijbiomac.2025.144106. Online ahead of print.

ABSTRACT

Melioidosis, also known as Whitmore's disease, is caused by the deadly pathogen Burkholderia pseudomallei and remains a significant global health concern, particularly in South Asia. The disease is contracted through exposure to contaminated soil, water, air, and food. Infected individuals often present with abscesses in internal organs such as the lungs, spleen, and liver, and in soft tissues, with severe cases leading to septic shock and acute pneumonia. The rising incidence and mortality rates, coupled with B. pseudomallei's ability to form biofilms and develop resistance to antibiotics like cephalosporins, make treatment increasingly challenging. This highlights the urgent need for novel therapeutic approaches. D-Alanine-D-Alanine ligase (Ddl), a crucial enzyme involved in the final stage of bacterial cell wall synthesis, which protects the pathogen from the hostile cellular environment of the host. While many bacteria have two isoforms of this enzyme, B. pseudomallei possesses only the DdlB isoform, presenting a significant vulnerability. Our study represents the first successful attempt to target DdlB through a combination of molecular docking and molecular dynamics simulations. These investigations provide strong evidence that Conivaptan acts as an effective inhibitor of DdlB, offering a novel therapeutic approach for combating melioidosis.

PMID:40393604 | DOI:10.1016/j.ijbiomac.2025.144106

ChemMedChem. 2025 May 20:e202500117. doi: 10.1002/cmdc.202500117. Online ahead of print.

ABSTRACT

Cathepsins are lysosomal proteases with well-documented roles in the progression of various cancers. Among them, cathepsin B (CTSB), a cysteine protease, is notably involved in the development of breast cancer and neuroblastoma. In this study, we explored the potential of darifenacin as a repurposed therapeutic targeting CTSB, using molecular docking and simulation studies which demonstrated a significantly lower binding energy against CTSB (-456.268 kJ/mol) compared to its known inhibitor, aloxistatin (-36.601 kJ/mol). The cytotoxic efficacy of darifenacin was evaluated on IMR-32 (neuroblastoma) and MCF-7 (breast cancer) cells, yielding half-maximal inhibitory concentrations (IC50) of 38.14 and 39.96 µM, respectively. Darifenacin effectively inhibited CTSB enzymatic activity by ~1.82 and ~1.75-fold in IMR-32 and MCF-7 cells, respectively, triggering intracellular ROS generation, mitochondrial membrane potential depolarization, and cell cycle arrest. These events culminated in apoptosis-mediated cell death, with apoptotic populations reaching 51.39% in IMR-32 and 40.6% in MCF-7 cells, respectively. Additionally, darifenacin disrupted lipid droplet accumulation, cellular migration, and colony and sphere-forming abilities in both cell lines. Overall, this study identifies darifenacin as a promising therapeutic agent against CTSB-driven cancer progression.

PMID:40393029 | DOI:10.1002/cmdc.202500117

PLoS One. 2025 May 20;20(5):e0323761. doi: 10.1371/journal.pone.0323761. eCollection 2025.

ABSTRACT

Parkinson's disease (PD) is an increasingly prevalent neurologic condition for which symptomatic, but not preventative, treatment is available. Drug repurposing is an innovate drug discovery method that uncovers existing therapeutics to treat or prevent conditions for which they are not currently indicated, a method that could be applied to incurable diseases such as PD. A knowledge graph artificial intelligence prediction system was used to select potential drugs that could be used to treat or prevent PD, and amphetamine was identified as the strongest candidate. Retrospective cohort analysis on a large, electronic health record database of deidentified patients with attention deficit hyperactive disorder (the main diagnosis for which amphetamine is prescribed) revealed a significantly reduced hazard of developing PD in patients prescribed amphetamine versus patients not prescribed amphetamine at 2, 4, and 6 years: Hazard Ratio (95% Confidence Interval) = 0.59 (0.36, 0.98), 0.63 (0.42, 0.93), and 0.55 (0.38, 0.79). Pathway enrichment analysis confirmed that amphetamine targets many of the biochemical processes implicated in PD, such as dopaminergic synapses and neurodegeneration. Together, these observational findings suggest that therapeutic and legal amphetamine use may reduce the risk of developing PD, in contrast to previous work that found the inverse relationship in patients using amphetamine recreationally.

PMID:40392924 | DOI:10.1371/journal.pone.0323761

IEEE J Biomed Health Inform. 2025 May 20;PP. doi: 10.1109/JBHI.2025.3571801. Online ahead of print.

ABSTRACT

Drug repositioning, which identifies new therapeutic potential of approved drugs, is pivotal in accelerating drug discovery. Recently, growing efforts are devoted to applying graph neural networks (GNNs) for effectively modeling drug-disease associations (DDAs). However, current GNN-based methods are generally designed for unsigned graphs and fail to gain complementary insights provided by negative links. Despite the proposal of sign-aware GNNs in general fields, there exist two intractable challenges when indiscriminately deploying prior solutions into drug repositioning. (i) How to explicitly connect the nodes within the same set (disease-disease and drug-drug)? (ii) How to design the contrastive learning objective for signed graphs? To this end, we propose a novel sign-aware graph contrastive learning approach, namely SIGDR, which takes both the positive and negative links from signed biological networks into consideration to identify underlying DDAs. To handle the first challenge, we measure the drug and disease similarity and form signed unipartite graphs according to similarity scores. For the second challenge, a signed bipartite graph is then constructed from the annotated DDA dataset. Through dividing above obtained signed graphs into positive and negative subgraphs respectively, we devise the inter-view contrastive learning auxiliary task to enhance the consistency of node representations derived from partitioned subgraphs with the same link type. Extensive experiments conducted on three benchmarks under 10-fold cross-validation demonstrate the model effectiveness. Source code and datasets are available at https://github.com/OleCui/paper_SIGDR.

PMID:40392637 | DOI:10.1109/JBHI.2025.3571801

J Neurooncol. 2025 May 20. doi: 10.1007/s11060-025-05082-1. Online ahead of print.

ABSTRACT

The presence of hormonal receptors in meningiomas has been known for decades. More recently, evidence has shown increased prevalence of meningiomas in patients taking certain types of hormonal treatments, such as oral contraceptives, progestins or hormone replacement therapy. Epidemiological evidence suggests that patients undergoing hormonal therapy harbor higher mutational rates of the oncogene PIK3CA. Due to the relative paucity of literature describing the intersection of hormone therapy and mutated PIK3CA pathways in meningioma, we have conducted a narrative review on this topic. Similarly, the clinical trial landscape for hormonal therapies for meningioma currently focuses on somatostatin receptor-targeted therapies and peptide receptor radionucleotide therapy, and the PIK3CA-hormonal signaling axis has not been explicitly targeted. Given the role of PIK3CA mutations in promoting cancer progression in other hormone-sensitive tumors, such as breast and prostate cancer, exploring this axis could inform drug repurposing including hormonal therapy specifically for these tumors.

PMID:40392516 | DOI:10.1007/s11060-025-05082-1

Bioinformatics. 2025 May 20:btaf311. doi: 10.1093/bioinformatics/btaf311. Online ahead of print.

ABSTRACT

MOTIVATION: Single-cell and spatial transcriptomics provide unprecedented insight into diseases. Pharmacotranscriptomic approaches are powerful tools that leverage gene expression data for drug repurposing and discovery. Multiple databases attempt to connect human cellular transcriptional responses to small molecules for use in transcriptome-based drug discovery efforts. However, preclinical research often requires in vivo experiments in non-human species, which makes utilizing such valuable resources difficult. To facilitate both human orthologous conversion of non-human transcriptomes and the application of pharmacotranscriptomic databases to pre-clinical research models, we introduce OrthologAL. OrthologAL interfaces with BioMart to access different gene sets from the Ensembl database, allowing for ortholog conversion without the need for user-generated code.

RESULTS: Researchers can input their single-cell or other high-dimensional gene expression data from any species as a Seurat object, and OrthologAL will output a human ortholog-converted Seurat object for download and use. To demonstrate the utility of this application, we tested OrthologAL using single-cell, single-nuclei, and spatial transcriptomic data derived from common preclinical models, including patient-derived orthotopic xenografts of medulloblastoma, and mouse and rat models of spinal cord injury. OrthologAL can convert these data types efficiently to that of corresponding orthologs while preserving the dimensional architecture of the original non-human expression data. OrthologAL will be broadly useful for the simple conversion of Seurat objects and for applying preclinical, high-dimensional transcriptomics data to functional human-derived small molecule predictions.

AVAILABILITY: OrthologAL is available for download as an R package with functions to launch the Shiny GUI at https://github.com/AyadLab/OrthologAL or via Zenodo at https://doi.org/10.5281/zenodo.15225041. The medulloblastoma single-cell transcriptomics data were downloaded from the NCBI Gene Expression Omnibus with the identifier GSE129730. 10X Visium data of medulloblastoma PDX mouse models from Vo et al. were acquired by contacting the authors, and the raw data are available from ArrayExpress under the identifier E-MTAB-11720. The single-cell and single-nuclei transcriptomics data of rat and mouse spinal-cord injury were acquired from the Gene Expression Omnibus under the identifiers GSE213240 and GSE234774.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:40392208 | DOI:10.1093/bioinformatics/btaf311

Future Med Chem. 2025 May 20:1-17. doi: 10.1080/17568919.2025.2507564. Online ahead of print.

ABSTRACT

The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling pathway is essential for controlling immune function, blood cell formation, and cell growth. Dysregulation of this pathway is implicated in various diseases, including hematologic malignancies, autoimmune disorders, and chronic inflammatory conditions. This review provides a comprehensive overview of the structural and functional aspects of JAK/STAT signaling, with a particular focus on the role of JAK2. This manuscript explores the primary regulators of the JAK/STAT pathway, such as Suppressors Of Cytokine Signaling (SOCS), Protein Inhibitors of Activated STATs (PIAS), and Protein Tyrosine Phosphatases (PTPs), which play a crucial role in maintaining cellular balance and stability. Additionally, the therapeutic landscape of JAK2 inhibitors is explored, covering both approved and investigational drugs, including their mechanisms of action, efficacy, and safety profiles. Emerging strategies such as drug repositioning using computational approaches and experimental validation are also highlighted. By integrating insights from molecular docking studies, machine learning models, and kinase assays, this review emphasizes the potential of JAK2 inhibitors in disease management.

PMID:40392133 | DOI:10.1080/17568919.2025.2507564

J Antimicrob Chemother. 2025 May 20:dkaf157. doi: 10.1093/jac/dkaf157. Online ahead of print.

ABSTRACT

BACKGROUND: Bacterial vaginosis (BV) is associated with significant reproductive health risks and high recurrence rates after standard antibiotic treatment. Sulfadoxine/pyrimethamine, an antimalarial drug, demonstrated unexpected clearance of BV in clinical trials, suggesting potential antimicrobial effects. Drug repurposing, which leverages existing drugs for new therapeutic applications, offers a promising approach to address the challenges of antimicrobial resistance and high recurrence rates in BV.

OBJECTIVE: To determine the in vitro activity of sulfadoxine/pyrimethamine and its components, sulfadoxine and pyrimethamine, on key species associated with BV.

METHODS: Minimum inhibitory concentration (MIC) and minimum bactericidal concentration were determined for sulfadoxine/pyrimethamine (20:1 ratio), sulfadoxine, pyrimethamine, and standard-of-care antibiotics, metronidazole and clindamycin, against BV-associated species (Gardnerella spp., Fannyhessea vaginae, Prevotella bivia) and Lactobacillus crispatus (vaginal health marker). Gardnerella biofilms were also exposed to sulfadoxine/pyrimethamine, pyrimethamine, or metronidazole, and biofilm biomass and biofilm cells culturability were assessed.

RESULTS: Sulfadoxine had no effect, while pyrimethamine inhibited all Gardnerella strains with MIC values ranging from 0.125 to 4 mg/L, lower than MICs observed for metronidazole (2-128 mg/L). Pyrimethamine also outperformed metronidazole in inhibiting biofilm mass accumulation and reducing biofilm culturable cells in 3/4 Gardnerella strains. Sulfadoxine/pyrimethamine presented lower MICs than metronidazole for 5/8 Gardnerella strains. Sulfadoxine, pyrimethamine, and sulfadoxine/pyrimethamine showed no activity against other BV-associated species or L. crispatus.

CONCLUSIONS: These findings suggest that pyrimethamine (and sulfadoxine/pyrimethamine) could be promising alternative or adjuvant therapies for BV, warranting further clinical trials.

PMID:40391646 | DOI:10.1093/jac/dkaf157