J Transl Med. 2025 Jul 8;23(1):753. doi: 10.1186/s12967-025-06783-x.

ABSTRACT

BACKGROUND: Drug repositioning offers a promising avenue for accelerating drug development and reducing costs. Recently, computational repositioning approaches have gained attraction for identifying potential drug-disease associations (DDAs). Biological entities such as drugs, genes, proteins, RNA, and diseases interact within a complex network. How to adequately extract the intrinsic relationships among them and accurately predict the drug-disease associations remains a challenge.

METHODS: In this study, we introduce MRDDA, a novel graph neural network model that utilizes multiple relations, for drug repositioning. First, we design a hybrid graph convolutional framework to capture both local and global representations of drugs and diseases. Subsequently, a meta-path-based approach is employed to capture high-order topological representations from these entities. Finally, we present a layer-wise attention mechanism to integrate embeddings from various layers.

RESULTS: The MRDDA model demonstrated superior performance in predicting drug-disease associations compared to existing methods, achieving higher results during the 10-fold cross-validation on three benchmark datasets. Notably, in our case studies focusing on Alzheimer's disease and breast cancer, MRDDA effectively identified several promising drug candidates that were previously unrecognized for these conditions. Additionally, molecular docking experiments reinforced our results by confirming the binding affinities and interactions between selected drugs and their target diseases, suggesting a solid basis for further experimental studies.

CONCLUSION: MRDDA offers an innovative framework for drug repositioning by effectively modeling and predicting drug-disease associations through advanced graph neural network techniques. The model's ability to integrate multi-relational data with greater accuracy paves the way for more efficient identification of potential therapeutic uses for existing drugs, ultimately contributing to the acceleration of drug development and reduced costs in the pharmaceutical industry.

PMID:40629423 | DOI:10.1186/s12967-025-06783-x

Curr Pharm Des. 2025 Jul 7. doi: 10.2174/0113816128372513250616182826. Online ahead of print.

ABSTRACT

BACKGROUND: Ulcerative colitis (UC) is an inflammatory disorder of the large intestine characterized by inflammation in the mucosal tissue of the colon and rectal area. In the present pilot study, we assessed the efficacy of combining mebendazole with mesalamine in moderate UC patients.

METHODS: In the present exploratory pilot trial, designed to assess both the safety and preliminary efficacy of mebendazole, a total number of 10 moderate UC patients with Mayo scores ranging from 6 to 9 were enrolled. The participants were divided into two groups at random and were treated with 3 gr mesalamine per day plus 300 mg/day mebendazole or matching placebo for 3 months. The efficacy of treatment was assessed in 8 and 12-week timelines with Mayo score. Moreover, the safety of the given dose of mebendazole in UC patients was also assessed by laboratory tests.

RESULTS: The addition of mebendazole to the mesalamine in the treatment regimen of patients suffering from UC caused a greater decrease in the Mayo score of the patients compared to the mesalamine monotherapy at 8 and 12-week timelines. Despite this trend, statistical significance was not reached, likely due to the limited sample size. Moreover, all the patients in the mebendazole group experienced clinical remission at the 12-week timeline, but 4 of 5 patients in the placebo group experienced a clinical remission state, indicating that mebendazole caused a 20% increase in the clinical remission rate. As indicated by the results of the laboratory tests, the given dose of mebendazole showed no toxicity in the patients.

CONCLUSION: The addition of mebendazole to mesalamine for UC treatment appears to be a safe and potentially beneficial approach to enhance mesalamine's efficacy and reduce clinical symptoms. However, given the small sample size and the short study duration, further large-scale, long-term trials are necessary to validate these preliminary findings.

CLINICAL TRIAL REGISTRATION NUMBER: IRCT20220115053713N2.

PMID:40626541 | DOI:10.2174/0113816128372513250616182826

Interdiscip Sci. 2025 Jul 7. doi: 10.1007/s12539-025-00733-3. Online ahead of print.

ABSTRACT

Computational drug repurposing utilizes data analysis and predictive models to identify new uses for existing drugs and new drugs, significantly improving research efficiency and reducing costs compared to traditional screening methods. Due to the limitations of current computational models in extracting deep key features, we develop a novel drug repurposing model based on the deep non-negative matrix factorization (DNMF-DDA) to enhance the accuracy of drug-disease association predictions. The model leverages similarity and known association data to extract low-rank features from complex data spaces, allowing for the prediction of potential drug-disease associations. To improve performance for novel drugs, we apply the k-nearest neighbors (KNN) algorithm for preprocessing, increasing the density of the matrix's prior information. Next, we construct two integrated matrices based on the similarities of drugs and diseases, respectively, and the optimized association data. During deep matrix factorization, we incorporate graph Laplacian and relaxed regularization constraints to optimize local graph features. This multi-layer optimization enhances the model's understanding of complex drug-disease relationships, effectively mitigating the negative impact of insufficient prior information during cold-start tests. Furthermore, we incorporate non-negativity constraints to ensure that the prediction results are biologically meaningful. To evaluate the performance of DNMF-DDA, we conducted cold-start test and 10-fold cross-validation on three datasets and systematically compared it with five state-of-the-art drug repurposing methods. The results demonstrate that DNMF-DDA performs exceptionally well in predicting drug-disease associations, significantly outperforming existing approaches. Our proposed method not only efficiently handles high-dimensional data but also exhibits superior performance, providing new insights for drug development. Moreover, the case study further validated the significant practical value of the DNMF-DDA model in practical applications.

PMID:40624392 | DOI:10.1007/s12539-025-00733-3

Biochem Pharmacol. 2025 Jul 5:117120. doi: 10.1016/j.bcp.2025.117120. Online ahead of print.

ABSTRACT

Liver fibrosis (LF), driven by dysregulated macrophage polarization and extracellular matrix remodeling, represents a critical and unmet therapeutic challenge in chronic liver diseases. Despite decades of research, the lack of agents targeting core transcriptional regulators of fibrogenesis underscores the urgent need for mechanism-based interventions. An integrative analysis of three single-cell transcriptomic atlases identified Early Growth Response 1 (EGR1) and Signal Transducer and Activator of Transcription 3 (STAT3) as central transcriptional regulators that orchestrate pro-fibrotic macrophage polarization and the downstream activation of fibrogenic effectors such as Arginase 1 (Arg1), Fibronectin 1 (Fn1), Osteopontin (Spp1), and Thrombospondin 1 (Thbs1). By leveraging computer-aided drug design (CADD), multi-precision virtual screening of both the FDA-approved drug library and the TCMSP drug database identified Cidofovir and Pioglitazone as novel inhibitors selectively targeting EGR1 and STAT3, respectively. Molecular dynamics simulations confirmed stable binding interactions at their DNA-binding domains. Functional validation in macrophages showed that Cidofovir suppressed EGR1 signaling and downstream fibrotic gene expression, while Pioglitazone inhibited STAT3 activity and M2 macrophage polarization. In a murine LF model, dual therapy synergistically reduced collagen deposition and hepatic stellate cell activation, exhibiting superior efficacy compared to monotherapy. This study pioneers the therapeutic repositioning of Cidofovir and Pioglitazone as dual-target transcriptional inhibitors, disrupting the EGR1/STAT3-Fn1/Spp1/Thbs1 axis to attenuate fibrotic niche formation. Our "multi-omics to bedside" framework, empowered by computer-aided drug design, not only deciphers macrophage-centric fibrogenic networks but also delivers clinically translatable candidates, bridging the gap between computational drug discovery and precision antifibrotic therapy.

PMID:40623460 | DOI:10.1016/j.bcp.2025.117120

Cancer Prev Res (Phila). 2025 Jul 7. doi: 10.1158/1940-6207.CAPR-24-0558. Online ahead of print.

ABSTRACT

Identifying the presence of tumors at a very early stage or deciphering the process underlying their development can enable the interception of pro-malignant mechanisms underpinning cancer emergence, facilitating more effective prevention. Advances in molecular profiling allow the detection of genetic, epigenetic, immune, and microenvironmental alterations associated with cancer risk. Liquid biopsy permits non-invasive analysis of circulating tumor cells, nucleic acids, immune cells, extracellular vesicles, proteins, cytokines, and metabolites, while metagenome analysis facilitates gut microbiota profiling. Multi-cancer early detection (MCED) assays broaden this approach, capturing signals from multiple malignancies using a single blood sample. These technologies go beyond genomics, addressing immune dysregulation and metabolic shifts and may help identify gut microbiota imbalances. Clonal hematopoiesis of indeterminate potential (CHIP) gets increasing recognition of biomarker. Cardiovascular risk scores based on multiple parameters are an inspiring example The analysis of a combination of cancer drivers and enablers should provide a more sensitive and personalized measure of cancer prodromic profiles. Artificial intelligence will further support this transition by integrating molecular, immune, and metabolic data to develop individualized risk profiles. This shift from single-cancer detection to integrated, mechanism-based screening fosters a more proactive prevention model.. This combination early detection empowers cancer interception by using strategies including lifestyle modification, nutritional optimization, drug repurposing, pharmacologic interventions, and targeted chemoprevention. Moving beyond single parameters analysis and organ-specific screening, this multidimensional approach advances early detection and interception as practical clinical goals, facilitating the fundamental aim of positioning prevention at the forefront of oncology.

PMID:40621774 | DOI:10.1158/1940-6207.CAPR-24-0558

Brain Behav. 2025 Jul;15(7):e70664. doi: 10.1002/brb3.70664.

ABSTRACT

INTRODUCTION: The risk of attention-deficit/hyperactivity disorder (ADHD) may involve genetic regulation by specific brain cells in the prefrontal cortex, but the causal associations are currently unclear.

METHODS: We integrated single-cell cis-expression quantitative trait loci (cis-eQTLs) from the prefrontal cortex with ADHD genome-wide association studies (GWASs). Using Mendelian randomization (MR) and Bayesian colocalization analyses, we assessed how brain cell-specific gene expression regulation affects ADHD susceptibility. We also examined the association between brain cell-type proportion and ADHD risk and used bioinformatics analyses to explore risk gene functions and identify potential drug-repurposing targets.

RESULTS: Single-cell eQTL MR analysis revealed that brain cell-specific gene regulation was causally linked to ADHD risk. For example, astrocyte-specific VIM expression was significantly associated with increased ADHD risk (β = 0.167, SE = 0.0388, p = 1.63 × 10-⁵). Further MR analysis of ADHD subtypes revealed that certain associations exhibited stronger causal effects in childhood, late-diagnosed, or persistent ADHD. Bayesian colocalization analysis further supported 24 unique genes, including VIM in astrocytes (PPH4 = 90.8%), which showed strong evidence of shared genetic signals with ADHD. The proportions of inhibitory neurons and oligodendrocytes in the prefrontal cortex were associated with specific ADHD subtypes. Bioinformatics analyses showed that risk genes were enriched in certain brain cell types and pathways relevant to ADHD pathogenesis, aligning with MR findings.

CONCLUSION: Our results identify 24 cell-specific genes in the prefrontal cortex that may mediate ADHD risk and highlight promising molecular targets for therapeutic development.

PMID:40621632 | DOI:10.1002/brb3.70664

Biochem Pharmacol. 2025 Jul 4:117118. doi: 10.1016/j.bcp.2025.117118. Online ahead of print.

ABSTRACT

Repurposing antitumor drugs for non-oncological diseases has emerged as a promising strategy to address unmet medical needs across diverse therapeutic areas. These drugs, originally developed to target cancer-related pathways, have demonstrated potential in treating various conditions by modulating critical biological processes. This review systematically explores innovative approaches to optimize drug repurposing and investigates the therapeutic potential of clinically approved antitumor agents in managing a broad spectrum of diseases, including infectious diseases, otorhinolaryngological and ophthalmic disorders, respiratory and urological conditions, digestive and reproductive system diseases, skin and musculoskeletal disorders, immunological diseases, nervous system disorders, cardiovascular and hematological conditions, among others. By summarizing the mechanisms of action, clinical trials, and challenges associated with repurposing antitumor drugs, this review highlights their broad applicability in treating complex diseases. The insights aim to inspire further research and guide future drug discovery, ultimately advancing translational medicine and expanding therapeutic possibilities.

PMID:40619023 | DOI:10.1016/j.bcp.2025.117118

Biochem Pharmacol. 2025 Jul 4:117126. doi: 10.1016/j.bcp.2025.117126. Online ahead of print.

ABSTRACT

Myeloid leukemia is a common form of blood cancer worldwide. Myeloid cell leukemia-1 (MCL-1), an anti-apoptotic member of the B-cell lymphoma-2 (BCL-2) family, is frequently overexpressed in various solid tumors and hematological cancers. Miconazole, a broad-spectrum anti-fungal agent, has exhibited anti-tumor properties against multiple cancer types, but its specific effects on leukemia remain unknown. The purpose of our research is to investigate whether miconazole targets MCL-1 to exert an anti-leukemic effect. Our research has demonstrated that miconazole directly binds to MCL-1 in HL60 and K562 cells, significantly inhibiting cell growth and decreasing MCL-1 protein levels, presumably by promoting MCL-1 degradation. Miconazole induces apoptosis, autophagy, and the production of reactive oxygen species (ROS). However, these effects can be attenuated by Z-VAD-FMK, 3-methyladenine (3-MA), and N-acetyl-L-cysteine (NAC). Meanwhile, miconazole-induced reduction of MCL-1 protein is reversed. Animal studies confirm the anti-myelocytic leukemia efficacy of miconazole in vivo. Unexpectedly, at low concentrations and with prolonged exposure, miconazole also promotes cell differentiation. This differentiation effect is positively associated with autophagy and ROS accumulation induced by miconazole, without altering MCL-1 expression. In conclusion, miconazole, identified through a drug repositioning (DR) approach, might be a potential therapeutic candidate for myeloid leukemia by either facilitating cell death or promoting cell differentiation.

PMID:40619022 | DOI:10.1016/j.bcp.2025.117126

J Biol Chem. 2025 Jul 4:110458. doi: 10.1016/j.jbc.2025.110458. Online ahead of print.

ABSTRACT

Vibrio cholerae has shaped the face of human civilization through at least seven pandemic waves. The current wave shows multidrug resistance, has produced enormous human and economic losses, as well as humanitarian crises, and has the potential to collapse the healthcare system of entire countries. Antibiotic resistance in this and other pathogens is an urgent threat that remains unaddressed due to the significant costs to develop new antibiotics. In this work, we have tested several FDA-approved phenazines and phenothiazines, and have identified that clofazimine (Lamprene) shows strong antibiotic effects against V. cholerae cells in culture and in an in vitro infection model, at concentrations well below the clinically-used doses in humans. Our results show that in an animal model, clofazimine is as effective as ampicillin in the treatment of cholerae. In addition, clofazimine shows strong antivirulence properties, almost completely inhibiting cholera toxin production. The characterization of V. cholerae metabolism allowed us to identify that clofazimine's main target in this pathogen is the respiratory complex NQR, an essential enzyme that plays a crucial role in energy metabolism, virulence factor production and multidrug resistance, which is widely distributed among pathogenic bacteria. Biochemical and computational analyses show that the structural target of clofazimine is the catalytically-active ubiquinone-binding site, which is a unique structural motif, not found in any human protein, making it an ideal pharmacologic target. These results show that clofazimine can be repurposed to treat cholera, and open opportunities to develop a novel class of antibiotics that target NQR.

PMID:40619003 | DOI:10.1016/j.jbc.2025.110458

Microb Pathog. 2025 Jul 3:107867. doi: 10.1016/j.micpath.2025.107867. Online ahead of print.

ABSTRACT

Protozoans are widely distributed unicellular eukaryotic microorganisms that are either free-living or inhabit other organisms as ecto- or endoparasites. Parasitic protozoans-associated diseases impose huge health complications especially in developing countries and are responsible for millions of morbidities and mortality worldwide each year. These diseases are often linked to poor hygiene, inadequate sanitation, and general neglect. For diagnosis of parasitic protozoans, microscopy, combined with various staining techniques, remains the gold standard due to its simplicity and accessibility. However, newer diagnostic methods, including molecular techniques and AI-based approaches, are gaining popularity for their higher sensitivity and ability to process multiple samples simultaneously. Current anti-protozoal drugs have limitations, accompanying toxic effects further the growing emergence of drug-resistant protozoan species, has made effective treatment ever more challenging. Advance research on target-specific, multi-dimensional vaccines and drug repurposing strategies offers hope for more effective disease control and management. Preventive measures, such as promoting health education, maintaining personal hygiene, and ensuring proper sanitation, are essential for reducing the spread of protozoan infections. This review article provides an overview of major parasitic protozoans, the factors facilitating their transmission, and recent advances in their diagnosis and control strategies.

PMID:40617448 | DOI:10.1016/j.micpath.2025.107867

EBioMedicine. 2025 Jul 4;118:105840. doi: 10.1016/j.ebiom.2025.105840. Online ahead of print.

ABSTRACT

BACKGROUND: Ataxia-telangiectasia (A-T) is a rare multisystem disease characterised by neurodegenerative cerebellar ataxia, lung disease, immune deficiency, high cancer risk, and mitochondrial dysfunction. A-T cells demonstrate defective endoplasmic reticulum-mitochondrial connectivity disrupting calcium homoeostasis and mitochondrial fusion, which are corrected in vitro by the triheptanoin metabolite, heptanoate.

METHODS: We performed a Phase 2a/b trial of triheptanoin with a three-arm placebo-controlled dose-escalation design. Doses escalated at 2-month intervals for 12 months in the sequence 0%, 10%, 20%, 35% of calculated caloric intake. The primary outcome was cell death in respiratory epithelial cells. Key secondary outcomes included scales for assessment and rating of ataxia (SARA), international cooperative ataxia rating scale (ICARS), speech and swallowing function, and novel biomarker discovery.

FINDINGS: 31 participants with A-T were enrolled aged from 4 to 37 years (median 16-years). For the maximum dose vs. placebo or no dose, significant improvements was observed for the primary outcome percent nasal cell death (mean difference (MD) = -9.7%, 95% confidence interval (CI) -16.0, 4.6). The SARA subscale kinetic function improved (MD = -5.8, 95% CI -10.4, -1.2), as did ICARS subscales gait (MD = -0.5, 95% CI -0.9, -0.1) and fine motor disturbance (MD = -2.7, 95% CI -4.3, -1.1). Speech intelligibility (MD = -12.8, 95% CI -21.2, -4.3) and swallowing safety (-0.9, 95% CI -1.6, -0.3) improved. Adverse events including abdominal pain, nausea, vomiting, and diarrhoea, requiring dose capping at 20%, were observed in 12 (38%) participants.

INTERPRETATION: Improvements in mitochondrial function in A-T cells in vivo in patients occurred after triheptanoin. The biomarkers neurofilament light chain and interferon signature stimulated gene scores may allow for monitoring of disease progression and treatment response.

FUNDING: Funded by Medical Researcher Futures Fund Australia (GA89314), The University of Queensland, Wesley Research Institute, and BrAshA-T.

PMID:40616902 | DOI:10.1016/j.ebiom.2025.105840

Biomed Pharmacother. 2025 Jul 4;189:118320. doi: 10.1016/j.biopha.2025.118320. Online ahead of print.

ABSTRACT

Building on clinical reports of symptomatic improvement in stroke patients following zolpidem administration, we investigated its neuroprotective efficacy and underlying mechanisms in a preclinical model of ischemia/reperfusion (I/R) injury. Pharmacokinetic analyses revealed that zolpidem preferentially accumulates in the hypothalamus and frontal cortex, with a notably prolonged half-life in the hypothalamus, suggesting region-specific drug retention. Early post-reperfusion administration of zolpidem (within 1.5 h) significantly reduced infarct volume, lowered glutamate levels, and improved motor recovery, underscoring a critical therapeutic window for intervention. Mechanistically, zolpidem enhanced phasic GABAergic signaling via α1 GABA-A receptors, reduced NKCC1 mRNA expression, and maintained neurochemical homeostasis without altering GABA transporter or receptor protein levels. Notably, zolpidem suppressed the frequency of cortical spreading depolarizations (CSDs), key propagators of secondary neuronal injury, without affecting wave dynamics, and modulated neurovascular coupling. Ischemic stroke outcomes are worsened by CSDs - waves of neuronal depolarization that propagate through compromised brain tissue and exacerbate secondary damage. These findings position zolpidem as a promising candidate for drug repurposing in stroke, uniquely targeting both early neuroprotection and longer-term functional recovery through selective modulation of GABAergic signaling and CSD suppression. Future clinical trials are warranted to define optimal therapeutic timing and maximize clinical benefit.

PMID:40616882 | DOI:10.1016/j.biopha.2025.118320

J Chemother. 2025 Jul 5:1-17. doi: 10.1080/1120009X.2025.2527464. Online ahead of print.

ABSTRACT

Acute myeloid leukemia (AML) is a heterogeneous malignancy specified by clonal proliferation of hematopoietic stem cells. This study identifies novel therapeutics for AML by integrating differential gene expression (DEG) and survival analyses. Publicly available GEO microarray datasets were analyzed, including data from 615 AML patients and 22 healthy controls. Multivariate Cox regression identified hazardous genes impacting survival. Protein-protein interaction networks using CytoScape revealed hub genes such as CCT5, ZBTB16, APP, and PTPN6. Functional enrichment revealed key AML-related pathways, such as PI3K/Akt and NF-kappaB signaling. Drug repurposing using the LINCS L1000CDS2 database highlighted potential therapeutics, including 16-Hydroxytriptolide and Tryptosthin AG-1478, with roles in reversing hazardous gene expression patterns. Additional candidates such as Vemurafenib, Parthenolide and Wortmannin, demonstrated promise as targeted agents. These findings underscore the potential of integrating bioinformatics and drug discovery to identify precision medicine in AML. Further studies are warranted to validate these targets and explore their clinical utility.

PMID:40616812 | DOI:10.1080/1120009X.2025.2527464

Epilepsia. 2025 Jul 5. doi: 10.1111/epi.18536. Online ahead of print.

ABSTRACT

OBJECTIVE: Drug-resistant epilepsy (DRE) affects >25 million people worldwide and is often associated with neuroinflammation. Increasing evidence links deficiency or malfunctioning of the enzyme phosphoglycerate dehydrogenase (PHGDH), which converts 3-phosphoglycerate to generate serine and the neurotransmitter glycine, with (drug-resistant) epilepsy. Moreover, PHGDH, which is primarily expressed in astrocytes within the brain, has been identified as a critical enzyme in driving macrophage polarization toward an anti-inflammatory state. Hence, PHGDH activators may be beneficial for treating DRE by exhibiting both antiseizure and anti-inflammatory activity. The objective of this study was to identify such PHGDH activators.

METHODS: We screened a drug repurposing library for PHGDH activators and assessed their antiseizure and anti-inflammatory properties using various zebrafish and mouse epilepsy models and explored the mechanistic consequences of activating PHGDH in a cell line, in astrocytes, and in zebrafish heads. Finally, we assessed the efficacy of clioquinol as add-on treatment in three severe DRE patients in a clinical open pilot proof-of-concept study.

RESULTS: We identified haloquinolines from a drug repurposing library as potent activators of PHGDH. The most promising haloquinoline clioquinol can increase the catalytic activity of PHGDH up to 2.5-fold, thereby increasing de novo glycine biosynthesis and resulting in reduced glutamate levels. Moreover, we show that clioquinol has PHGDH-dependent antiseizure activity as well as anti-inflammatory properties in vivo using various zebrafish and mouse epilepsy models. Finally, we demonstrate the efficacy of clioquinol as add-on treatment in severe DRE patients; two patients showed a 37%-47% reduction in seizure frequency, and all three patients noted a positive impact on quality of life and seizure severity.

SIGNIFICANCE: Increasing activity of PHGDH is a promising new approach to treat DRE.

PMID:40616775 | DOI:10.1111/epi.18536

Neuroscience. 2025 Jul 2:S0306-4522(25)00751-1. doi: 10.1016/j.neuroscience.2025.06.063. Online ahead of print.

ABSTRACT

BACKGROUND: The newest glioma classification in WHO 2021 emphasizes the importance of gene mutations in the glioma molecular pathogenesis. Our research aims to look for new glioma-related genes that have the potential to be therapeutic targets.

METHODS: We applied Mendelian randomization and colocalization analysis to identify the target genes. Artificial intelligence-based methods were employed to evaluate the prognostic significance of the target gene in patient outcomes. Bioinformatics was then utilized to explore the expression and function of the gene in gliomas. Finally, we found the gene targeted drugs by Drug Signatures Database which is primarily used to explore the effects of drugs on gene expression and drug repurposing, and carried out molecular docking to evaluate the interaction between gene and drugs.

RESULTS: Bestrophin-1 (BEST1) is the only gene that passes the MR and colocalization analysis. Bioinformatics analyses demonstrated that BEST1 showed significant associations in glioma. We identified chlorothiazide as a therapeutic target drug associated with BEST1, which has not been previously studied in gliomas.

CONCLUSION: Our findings validate BEST1 as a potential therapeutic target for gliomas through various approaches. We predicted chlorothiazide as a fresh candidate for glioma treatment and provided a new direction for the research in the future.

PMID:40614923 | DOI:10.1016/j.neuroscience.2025.06.063

Int Immunopharmacol. 2025 Jul 3;162:115135. doi: 10.1016/j.intimp.2025.115135. Online ahead of print.

ABSTRACT

BACKGROUND: Given the potential for persistent inflammation to induce severe systemic inflammatory consequences, the development of new drugs for the early inflammatory cascade of acute pancreatitis (AP) is particularly important. The aim of this study was to investigate the activity of the JAK inhibitor tofacitinib (TOFA) against AP.

METHODS: In vivo, TOFA efficacy against AP was assessed in a mouse model induced by the intraperitoneal injection of caerulein and retrograde pancreatic duct infusion of sodium taurocholate (STC). In vitro, we evaluated the effect of TOFA on the polarization of mouse macrophages (RAW264.7) exposed to lipopolysaccharide (LPS) alone or in combination with IFN-γ. In addition, to verify that TOFA improves AP via JAK/STAT inhibition, RNA-Seq was used to explore potential signalling cascades that inhibit M1 polarization.

RESULTS: TOFA significantly improved pancreatic injury and the inflammatory response in two AP mouse models by inhibiting M1 macrophage polarization in vivo and in vitro. The inhibitory effects of TOFA were mediated by JAK/STAT pathway suppression (reducing p-STAT1 and p-STAT3). Furthermore, after the administration of filgotinib (a JAK1 inhibitor), TOFA still significantly inhibited macrophage M1 polarization. RNA-Seq, qPCR and Western blotting subsequently confirmed that TOFA also has inhibitory effects on the emerging NOD-like receptor signalling pathway. This is primarily reflected in the inhibition of GBP2, GBP5, NLRP3, GSDMD-N and CASP 1 protein expression.

CONCLUSIONS: TOFA improves macrophage M1 polarization and the associated inflammatory storm stimulated by AP by inhibiting the primary JAK/STAT pathway and the emerging NOD-like receptor pathway. This study expands the new use of the old drug TOFA in the clinical treatment of AP.

PMID:40614601 | DOI:10.1016/j.intimp.2025.115135

Mol Divers. 2025 Jul 4. doi: 10.1007/s11030-025-11248-w. Online ahead of print.

ABSTRACT

Traditional or de novo drug discovery is a time-consuming, costly, and high-investment process due to the high attrition rate. Therefore, many trials are conducted to reuse existing drugs to treat pressing conditions and diseases, since their safety profiles and pharmacokinetics are already available. Drug repurposing (DR) (also known as drug repositioning) is a strategy to identify a new indication of existing or already-approved drugs, beyond the scope of their original use. Various in silico-based computational and activity-based experimental approaches to incorporate available resources have been suggested for gaining a better understanding of disease mechanisms and the identification of repurposed drug candidates for personalized pharmacotherapy. This strategy is highly efficient, timesaving, low-cost, and minimum risk of failure. It maximizes the therapeutic value of a drug and consequently increases the success rate. This review introduced publicly available databases for drug repositioning and summarized the approaches taken for drug repositioning. Also, it highlighted and compared their characteristics, which should be addressed for the future realization of drug repositioning.

PMID:40613877 | DOI:10.1007/s11030-025-11248-w

Parasite. 2025;32:42. doi: 10.1051/parasite/2025035. Epub 2025 Jul 4.

ABSTRACT

Cutaneous leishmaniasis presents a significant challenge to public health due to its diverse clinical manifestations, resistance development, and treatment-related adverse effects. Here, we examined the efficacy of ivermectin, moxidectin (MOX), afoxolaner, and permethrin against all stages of Leishmania tropica and THP-1 cells. We also assessed the potential for resistance acquisition after 15 rounds of artificial selection. To elucidate the mode of action of MOX, we employed RNA sequencing, molecular dynamics simulation, and chloride flux assays. Additionally, we evaluated the therapeutic index of MOX using the Galleria mellonella infection model. MOX demonstrated the highest selectivity index against leishmaniasis (promastigotes: 0.58 μM; amastigotes: 0.96 μM; host cells: 60.29 μM). Moreover, MOX exhibited the lowest resistance acquisition in both promastigotes and intracellular amastigotes after 15 rounds of artificial selection, with resistance ratios of 17.23 and 4.59, respectively. Post-exposure to MOX, differential gene expression profiles showed both stage-specific and stage-unspecific enrichment of gene families involved in crucial biological processes. Moreover, molecular dynamics simulations revealed a potential neutralizing effect of MOX on the chloride channel of L. tropica. Specifically, MOX binds to the selectivity filter, potentially disrupting the osmotic equilibrium and thereby killing the parasite. The in vivo introduction of MOX significantly inhibited the growth of L. tropica in G. mellonella larvae, resulting in decreased rates of mortality and melanization. These findings indicate that MOX is a promising candidate for the treatment of L. tropica infections, warranting further investigation and potential consideration for clinical use.

PMID:40613607 | DOI:10.1051/parasite/2025035

Oncol Res. 2025 Jun 26;33(7):1781-1796. doi: 10.32604/or.2025.063717. eCollection 2025.

ABSTRACT

BACKGROUND: The increasing incidence of cancers and infectious diseases worldwide presents a significant public health challenge that requires immediate intervention. Our strategy to tackle this issue involves the development of pharmaceutical formulations that combine phytopolyphenols (P), targeted drugs (T), and metal ions (M), collectively referred to as PTM regimens. The diverse pharmacological properties of PTM regimens are hypothesized to effectively reduce the risk factors associated with both cancers and infectious diseases.

METHODS: The effects of the pharmaceutical agents on the proliferation of cultured cancer cells and pathogens were assessed after 72 h and 48 h, respectively, using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay and optical density at 600 nm (OD600). The synergistic effects of drug combinations were evaluated by combination index (CI), where CI < 1 indicates synergism, CI = 1 indicates addition, and CI > 1 indicates antagonism. Efficacy index (EI) was also calculated. Assays of efflux pump ATPase activities were conducted using a colorimetric method.

RESULTS: This study evaluated the anticancer and antibacterial efficacy of PTM regimens that included phytopolyphenols (specifically curcumin (C) and green tea polyphenols (G)), repurposed drugs (memantine (Mem), thioridazine (TRZ), cisplatin (Cis), and 5-fluorouracil (5FU)), and ZnSO4 (Zn) across three cultured cancer cell lines and four cultured pathogens. The most effective regimens, GC•Mem•Zn and GC•TRZ•Zn, significantly enhanced the anticancer efficacy (EI) of cisplatin across the three cancer lines (OECM-1, A549 and DLD-1) by 7, 11 and 21; 7, 9, and 17 fold, respectively, while the enhancements for 5-fluorouracil were 5, 6 and 12; 5, 5 and 9 fold, respectively. Furthermore, these PTM regimens demonstrated substantial synergistic inhibition of Na+-K+-Mg2+-ATPase and Mg2+-ATPase in the cultured cancer cells, as well as a reduction in biofilm formation by the four cultured pathogens, suggesting their potential to address the challenges of multidrug resistance in cancers and infectious diseases.

CONCLUSION: Given that all drugs incorporated in the PTM regimens have been clinically validated for safety and efficacy, particularly regarding their synergistic selective anticancer efficacy, inhibition of efflux pump ATPase, and antibiofilm formation of pathogens, these regimens may offer a promising therapeutic strategy to alleviate the severe side effects and drug resistance typically associated with chemotherapeutic agents. Further preclinical and clinical investigations are warranted.

PMID:40612861 | PMC:PMC12215547 | DOI:10.32604/or.2025.063717

Int J Biol Sci. 2025 Jun 9;21(9):3949-3967. doi: 10.7150/ijbs.112645. eCollection 2025.

ABSTRACT

There is an urgent need for new therapeutic strategies against aggressive triple-negative breast cancer (TNBC), and drug repurposing offers a promising, time- and cost-effective solution. We previously reported that TGFβ leads to the tumorigenic role of NDRG1 in TNBC. Here, we aimed to identify drugs that mimic the transcriptomic signature after the inhibition of TGFβ-induced NDRG1 and to determine their antitumor properties. The transcriptomic signature was obtained by RNA sequencing after gene silencing of TGFβ-induced NDRG1 expression in TNBC cells. For the drug repositioning study, the transcriptome was further computationally analyzed by using the Connectivity Map tool. Efavirenz, ouabain, and vinburnine were selected as the repurposed drug candidates to evaluate their therapeutic potential in TNBC models as monotherapies and pairwise combinations. We determined that the candidate drugs significantly reduced tumor cell proliferation, cancer stem cells, self-renewal, clonogenic properties, and migration abilities in TNBC cell lines through the blockade of AKT. Importantly, we validated their translational potential in TNBC patient-derived xenograft organoids in combination with docetaxel. After validating that the drugs decreased p-AKT and Ki67, we demonstrated their antitumor activity in combination with docetaxel in organoids. In addition, drugs also showed efficacy in a docetaxel-resistant TNBC model, supporting their potential to overcome chemoresistance. In conclusion, these findings demonstrate the potential of efavirenz, ouabain, and vinburnine as repurposed agents capable of inhibiting TNBC cell proliferation, stemness, and migration. Their synergistic effects with docetaxel in organoid cultures further underscore their translational relevance and highlight a promising strategy for combination therapies to improve TNBC treatment.

PMID:40612674 | PMC:PMC12223764 | DOI:10.7150/ijbs.112645