Sci Adv. 2025 Mar 14;11(11):eadr3757. doi: 10.1126/sciadv.adr3757. Epub 2025 Mar 12.

ABSTRACT

Brain age gap (BAG), the deviation between estimated brain age and chronological age, is a promising marker of brain health. However, the genetic architecture and reliable targets for brain aging remains poorly understood. In this study, we estimate magnetic resonance imaging (MRI)-based brain age using deep learning models trained on the UK Biobank and validated with three external datasets. A genome-wide association study for BAG identified two unreported loci and seven previously reported loci. By integrating Mendelian Randomization (MR) and colocalization analysis on eQTL and pQTL data, we prioritized seven genetically supported druggable genes, including MAPT, TNFSF12, GZMB, SIRPB1, GNLY, NMB, and C1RL, as promising targets for brain aging. We rediscovered 13 potential drugs with evidence from clinical trials of aging and prioritized several drugs with strong genetic support. Our study provides insights into the genetic basis of brain aging, potentially facilitating drug development for brain aging to extend the health span.

PMID:40073132 | DOI:10.1126/sciadv.adr3757

J Chem Inf Model. 2025 Mar 12. doi: 10.1021/acs.jcim.4c02424. Online ahead of print.

ABSTRACT

The goal of drug repositioning is to expedite the drug development process by finding novel therapeutic applications for approved drugs. Using multifeature learning, different computational drug repositioning techniques have recently been introduced to predict possible drug-disease relationships. Nevertheless, current graph-based methods tend to model drug-disease interaction relationships without considering the semantic influence of node-specific side information on graphs. These approaches also suffer from the noise and sparsity inherent in the data. To address these limitations, we propose MDGCN, a novel drug repositioning method that incorporates multidependency graph convolutional networks and contrastive learning. Based on drug and disease similarity matrices and the drug-disease relationships matrix, this approach constructs multidependency graphs. It subsequently employs graph convolutional networks to spread side information between various graphs in each layer. Meanwhile, the weak supervision of drug-disease connections is effectively addressed by introducing cross-view and cross-layer contrastive learning to align node embedding across various views. Extensive experiments show that MDGCN performs better in drug-disease association prediction than seven advanced methods, offering strong support for investigating novel therapeutic indications for medications of interest.

PMID:40071716 | DOI:10.1021/acs.jcim.4c02424

Rheumatology (Oxford). 2025 Mar 1;64(Supplement_1):i109-i111. doi: 10.1093/rheumatology/keae387.

ABSTRACT

The search for targeted therapies and biomarkers for immune-mediated systemic vasculitis requires detailed understanding of molecular pathogenesis. Whilst candidate approaches have identified new opportunities for drug repurposing, they also miss novel approaches for targeting critical immunological or stromal pathways. On the other hand, bulk transcriptional profiling may fail to capture differences in cellular composition and, depending on the cell source profiled, miss important changes within inflamed vascular tissue. The past decade has seen major advances in both experimental techniques and analytical tools that enable multi-dimensional molecular profiling. Interrogation of the transcriptome and proteome is now possible at a single cell level, or at levels of spatial resolution within tissue that was previously unimaginable. As demonstrated during the presentations in the breakout session of the 21st International Vasculitis Workshop entitled Transcriptomic approaches to the study of systemic vasculitis, these techniques are revealing greater understanding of molecular underpinnings of the systemic vasculitides.

PMID:40071404 | DOI:10.1093/rheumatology/keae387

Chem Biol Drug Des. 2025 Mar;105(3):e70088. doi: 10.1111/cbdd.70088.

ABSTRACT

Methicillin-resistant Staphylococcus aureus (MRSA) achieves high-level resistance against β-lactam antibiotics through the expression of penicillin-binding protein 2a (PBP2a), which features a closed active site that impedes antibiotic binding. Herein, we implemented a strategy that combines drug repurposing with synergistic therapy to identify potential inhibitors targeting PBP2a's allosteric site from an FDA-approved drug database. Initially, retrospective verifications were conducted, employing different Glide docking methods (HTVS, SP, and XP) and two representative PBP2a structures. The combination of Glide SP and one representative PBP2a conformation showed the highest efficacy in identifying active compounds. The optimized parameters were then utilized to screen FDA-approved drugs, and 15 compounds were shortlisted for potential combination therapy with cefazolin, an ineffective cephalosporin against MRSA. Through biological assays-checkerboard, time-kill assays, and live/dead bacterial staining-we discovered that four compounds exhibited robust bactericidal activity (FICI < 0.5) compared to both untreated control and monotherapy with cefazolin alone. Scanning electron microscopy (SEM) confirmed that while cefazolin alone did not cause visible damage to MRSA cells, the combination treatment markedly induced cell lysis. Additional MM-GBSA studies underscored the strong binding affinity of mitoxantrone to the allosteric site. These findings introduce a combination therapy approach that potentially restores MRSA's susceptibility to β-lactam antibiotics.

PMID:40070213 | DOI:10.1111/cbdd.70088

Chem Biodivers. 2025 Mar 11:e202402883. doi: 10.1002/cbdv.202402883. Online ahead of print.

ABSTRACT

Zinc (Zn) ions play a crucial role in cancer therapy due to their ability to induce reactive oxygen species (ROS) generation, oxidative stress, and ferroptosis. Combining Zn ions with other therapeutic agents can significantly enhance their efficacy through synergistic mechanisms. This study explores the synergistic mechanism of Zn ions form pH-responsive ZIF-8 and repurposed drug Pimozide in tumor microenvironment mimic conditions. The synthesized ZIF-8 exhibited an average size distribution of 36 nm with 52.21 ± 1.86 % of encapsulation efficiency for Pimozide. Notably, the maximum drug release of 84.13% was observed at pH 6. Further, in-vitro cytotoxicity investigations revealed heightened efficacy of Pimozide-ZIF-8 formulations after 48 h of treatment. In addition, Pimozide-ZIF-8 concomitantly induced ferroptosis and apoptosis in MCF-7 cells at pH 6, underscoring the pharmacological potency of the composite structure. Complementary to these experimental findings, an in-silico network analysis was performed to uncover protein interaction networks of Zn ions and Pimozide, highlighting their multi-targeted action in cancer-related pathways. Altogether, this dual-action approach activates both ferroptosis and apoptosis, presenting a promising therapeutic strategy for breast cancer that offers enhanced efficacy and targeting through the combined effects of Zn ions and Pimozide.

PMID:40065747 | DOI:10.1002/cbdv.202402883

In Silico Pharmacol. 2025 Mar 6;13(1):41. doi: 10.1007/s40203-025-00323-7. eCollection 2025.

ABSTRACT

The Marburg virus (MARV), a member of the family Filoviridae, is a highly pathogenic virus causing severe hemorrhagic fever with extremely high mortality in humans and non-human primates. The MARV exhibits clinical and epidemiological features almost identical to those of the Ebola virus, no licensed vaccines or antiviral treatments have been developed yet for MARV. However, only a few treatments that remain uncertain of the disease are available to help bring a case for a new therapeutic approach. Considering the non-availability of any standard drug we have planned to identify potential inhibitors of VP24 (PDB ID: 4OR8) through a computational drug repurposing process. The workflow includes: identifying a druggable pocket on VP24, screening of FDA-approved antivirals via molecular docking, assessing the stability using molecular dynamics simulations, and estimating binding affinity through MM-PBSA calculations. After going through the analysis, the compound Bictegravir manifests as a hit compound which will undergo in vitro and in vivo validation to confirm its efficacy against MARV.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00323-7.

PMID:40061630 | PMC:PMC11885215 | DOI:10.1007/s40203-025-00323-7

bioRxiv [Preprint]. 2025 Feb 28:2025.02.26.640194. doi: 10.1101/2025.02.26.640194.

ABSTRACT

Despite numerous research efforts and several effective vaccines and therapies developed against COronaVIrus Disease 2019 (COVID-19), drug repurposing remains an attractive alternative to identify new treatments for SARS-CoV-2 virus variants and other viral infections that may emerge in the future. Cellular polyamines support viral propagation and tumor growth. Here we tested the antiviral activity of an irreversible inhibitor of polyamine biosynthesis, α-difluoromethylornithine (DFMO) and a non-steroidal anti-inflammatory drug (NSAID) Sulindac, which have been previously evaluated for colon cancer chemoprevention. The drugs were tested as single agents and in combination in human Calu-3 lung adenocarcinoma and Caco-2 colon adenocarcinoma cell lines and the K18-hACE2 transgenic mouse model of severe COVID-19. DFMO/Sulindac combination significantly suppressed SARS-CoV-2 N1 Nucleocapsid mRNA and ACE2 mRNA levels in the infected human cell lines by interacting synergistically when cells were pretreated with drugs and additively when treatment was applied to the infected cells. The antiviral activity of DFMO and Sulindac was tested in vivo as prophylaxis (drug supplementation at the doses equivalent to the human chemoprevention trial started 7 days before infection) or as treatment (drug supplementation started 24 hours post-infection). Prophylaxis with DFMO and Sulindac as single agents significantly increased survival rates in the young male mice (p=0.01, and p=0.027, respectively), and the combination was effective in the aged male mice (p=0.042). Young female mice benefited the most from the prophylaxis with Sulindac alone (p=0.001) and DFMO/Sulindac combination (p=0.018), while aged female mice did not benefit significantly from any interventions. The treatment regime was ineffective in suppressing SARS-CoV-2 infection in K18-hACE2 mice. Overall, animal studies demonstrated the protective age- and sex-dependent antiviral efficacy of DFMO and Sulindac against SARS-CoV-2.

PMID:40060444 | PMC:PMC11888430 | DOI:10.1101/2025.02.26.640194

J Biochem Mol Toxicol. 2025 Mar;39(3):e70204. doi: 10.1002/jbt.70204.

ABSTRACT

Sunitinib (SUN) is a chemotherapeutic agent showing renal toxicity that limits its clinical applications. The present research aimed to clarify the potential ameliorative effects of secukinumab (SEC) and dapagliflozin (DAPA) against SUN-induced renal toxicity and the underpinning molecular mechanisms. For this purpose, adult Wistar albino rats were received SUN (25 mg/kg 3 times/week, po) and co-treated with SEC (3 mg/kg/every 2 weeks, subcutaneously) or DAPA (10 mg/kg/day, po) for 4 weeks and compared with age-matched control group (CON). Markers of kidney functions were assessed in serum samples. Kidneys were harvested for biochemical and histological examination. Compared to CON group, SUN-treated rats displayed signs of kidney dysfunction along with renal histological changes that were ameliorated by SEC or DAPA. Both drugs significantly lowered the renal levels of IL-17, but SEC exerted more inhibitory effect than DAPA. Additionally, SUN-subjected rats showed significant increases in the renal expression of NLRP3 inflammasome and the other inflammatory mediators including IL-1β, END-1, and MCP-1. This was associated with marked decline of the renal levels of beclin-1. Co-treatment with SEC or DAPA significantly suppressed NLRP3-induced inflammation while enhanced beclin-1-mediated autophagy. The modulatory effect of DAPA on NLRP3 and beclin-1 was superior to that of SEC. Moreover, both drugs significantly and similarly attenuated the enhanced cleaved caspase-3 expression and interstitial fibrosis in renal tissue of SUN-subjected rats. Collectively, these findings may repurpose SEC and DAPA as candidate therapies to alleviate the renal toxicity of SUN and to rescue the renal functionality in SUN-treated cancer cases.

PMID:40059817 | DOI:10.1002/jbt.70204

Future Microbiol. 2025 Mar 9:1-13. doi: 10.1080/17460913.2025.2475639. Online ahead of print.

ABSTRACT

AIMS: To evaluate the antibacterial and antibiofilm activities of sodium ibuprofenate (NaI) and its hypertonic variant (NaIHS) against multidrug-resistant Gram-negative bacteria (MDR-GNB) and explore their potential to inhibit β-lactamase enzymes.

METHODS: Antibacterial activity was assessed using minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and time-kill assays. Antibiofilm activity was evaluated by measuring bacterial viability and biomass reduction in preformed biofilms. Scanning electron microscopy (SEM) was used to observe membrane effects. Molecular docking and molecular dynamics simulations were conducted to analyze the binding affinity of ibuprofen to the active sites of β-lactamases (CTX-M-15, KPC-2, OXA-23).

RESULTS: NaI exhibited bactericidal activity at concentrations of 25-75 mm, with Acinetobacter baumannii being the most susceptible. NaCl (≥0.5 M) enhanced bactericidal efficacy and lowered MBCs. Time-kill assays indicated rapid bacterial eradication within 2 hours, with NaIHS achieving similar results at lower concentrations. SEM confirmed membrane disruption. Both formulations reduced bacterial viability in biofilms, with NaIHS showing greater efficiency. In silico studies suggest ibuprofen may inhibit β-lactamases, with enhanced interactions in saline environments.

CONCLUSION: Sodium ibuprofenate, particularly in its hypertonic form, demonstrates strong antibacterial, antibiofilm, and potential β-lactamase inhibitory activity, making it a promising candidate for treating MDR-GNB infections.

PMID:40059403 | DOI:10.1080/17460913.2025.2475639

Life Sci. 2025 Mar 7:123548. doi: 10.1016/j.lfs.2025.123548. Online ahead of print.

ABSTRACT

AIMS: This study explores the association between the Wnt signaling pathway and T2DM, emphasizing the role of Tankyrase1 (TNKS1) in metabolic regulation. Using network pharmacology and computational approaches, it aims to identify potential FDA-approved drugs for repurposing as Wnt inhibitors to improve insulin sensitivity and reduce fat accumulation.

MATERIALS AND METHODS: Network pharmacology analysis was performed to explore the association between the Wnt pathway and T2DM, identifying Catenin Beta 1 (CTNBB1) as a key hub gene involved in disease progression. A 2D structural similarity search was conducted using reference tankyrase inhibitors (E7449 and XAV939). Potential drug candidates were subjected to molecular docking and 100 ns molecular dynamics (MD) simulations with the Tankyrase I (PDB ID: 4W6E) protein. The shortlisted compounds were further evaluated for Wnt inhibitory activity using the TCF/LEF reporter assay, while their anti-diabetic potential was assessed through a glucose uptake assay in L6 myoblast cells.

KEY FINDINGS: Niclosamide, Capmatinib, Esomeprazole, and Fenofibrate were identified as promising candidates with strong binding affinities and stable interactions with key amino acids (Gly1185, Ser1221, Tyr1224, Asp1198, Tyr1213, and His1201). Experimental validation through in-vitro Wnt inhibition and glucose uptake assays confirmed that drugs Fenofibrate and Conivaptan exhibited significant Wnt inhibitory activity, suggesting their potential role in modulating T2DM-related pathways.

SIGNIFICANCE: This study highlights the role of the Wnt signaling pathway in T2DM pathogenesis and identifies potential drug candidates for repurposing as Tankyrase1/Wnt inhibitors. The findings provide a foundation for further in-vivo investigations into the anti-diabetic potential of the identified drugs, paving the way for novel therapeutic strategies in T2DM management.

PMID:40058577 | DOI:10.1016/j.lfs.2025.123548

Redox Biol. 2025 Mar 3:103569. doi: 10.1016/j.redox.2025.103569. Online ahead of print.

ABSTRACT

Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-activated transcription factor regulating cellular defense against oxidative stress, thereby playing a pivotal role in maintaining cellular homeostasis. Its dysregulation is implicated in the progression of a wide array of human diseases, making NRF2 a compelling target for therapeutic interventions. However, challenges persist in drug discovery and safe targeting of NRF2, as unresolved questions remain especially regarding its context-specific role in diseases and off-target effects. This comprehensive review discusses the dualistic role of NRF2 in disease pathophysiology, covering its protective and/or destructive roles in autoimmune, respiratory, cardiovascular, and metabolic diseases, as well as diseases of the digestive system and cancer. Additionally, we also review the development of drugs that either activate or inhibit NRF2, discuss main barriers in translating NRF2-based therapies from bench to bedside, and consider the ways to monitor NRF2 activation in vivo.

PMID:40059038 | DOI:10.1016/j.redox.2025.103569

Biochimie. 2025 Mar 7:S0300-9084(25)00056-2. doi: 10.1016/j.biochi.2025.03.002. Online ahead of print.

ABSTRACT

Metformin, initially prescribed as an oral hypoglycemic medication for type 2 diabetes, has recently gained attention for its potential anticancer effects. Its history dates to 1918, when guanidine, a component of the traditional European herb Galega officinalis, was found to reduce glycemia. This review precisely examines the mechanisms underlying Metformin's anticancer effects across various neoplastic conditions. This investigation explores the complex interactions between metformin and major signaling pathways associated with carcinogenesis, including AMP-activated protein kinase (AMPK), mTOR, and insulin-like growth factor (IGF) pathways. The review emphasizes Metformin's diverse effects on angiogenesis, inflammation, apoptosis, and cellular metabolism in cancer cells. Additionally, new data on metformin's capacity to alter the tumor microenvironment and enhance immune surveillance systems against cancer are examined. The review underscores Metformin's potential for repurposing in oncology, emphasizing its clinical relevance as an adjuvant therapy for various cancers. The review provides insightful information about the complex anticancer mechanisms of metformin by combining data from preclinical and clinical studies. These findings not only broaden our knowledge of the effects of metformin but also open new avenues for oncology research and treatment developments.

PMID:40058683 | DOI:10.1016/j.biochi.2025.03.002

Comput Biol Med. 2025 Mar 6;189:109989. doi: 10.1016/j.compbiomed.2025.109989. Online ahead of print.

ABSTRACT

The Chikungunya virus (CHIKV) represents a significant global health threat, particularly in tropical regions, and no FDA-approved antiviral treatments are currently available. This study investigates the potential of Direct-Acting Antivirals (DAAs) and protease inhibitors (PIs) that have been developed for the hepatitis C virus (HCV) in treating CHIKV. We analyzed the binding of eight HCV DAAs to the nsP2 protease of CHIKV, which is essential for viral replication. Our findings suggest repurposing hepatitis C virus (HCV) antivirals, specifically Simeprevir (SIM) and voxilaprevir (VOX), could be effective against CHIKV. Through computational analyses, we observed their strong binding affinity to CHIKV's nsP2 protease, indicating the promising potential of repositioning these drugs for CHIKV treatment. To validate the results of our computational study, we evaluated the antiviral efficacy of SIM and VOX in vitro, both as monotherapies and in combination with ribavirin (RIBA). Our findings revealed that DAAs exert a multifaced effect by targeting different stages of the CHIKV life cycle. Furthermore, the synergistic effects suggest that combining SIM and VOX with RIBA may provide a more effective therapeutic strategy than using either drug alone. Further research is necessary to optimize treatment protocols and improve outcomes for patients affected by CHIKV.

PMID:40056839 | DOI:10.1016/j.compbiomed.2025.109989

In Silico Pharmacol. 2025 Mar 4;13(1):36. doi: 10.1007/s40203-025-00325-5. eCollection 2025.

ABSTRACT

Tuberculosis (TB), a major global health concern, even after significant advancements in diagnosis and treatment, causing millions of deaths annually and severely impacting the healthcare systems of developing nations. Moreover, the rise of drug-resistant strains further diminishes the efforts made to control the infection and to overcome this scenario, highly effective drugs are required. Identifying new therapeutic uses of existing drugs through drug repurposing can significantly shorten the time and cost. In the current study, using a computational experimental approach, near about 3104 FDA-approved drugs and active pharmaceutical ingredients from Selleckchem database were screened against Enhanced intracellular survival (Eis) protein, responsible for causing drug resistance by inhibiting the aminoglycoside drug activity. Based on the three-level screening and Molecular Mechanics generalized Born surface area (MM/GBSA) scores, five drugs including Isavuconazonium sulfate, Cefotiam Hexetil Hydrochloride, Enzastaurin (LY317615), Salbutamol sulfate (Albuterol), and Osimertinib (AZD9291) were considered as potential Eis inhibitors. The 500 ns MD simulation results revealed that all these Eis-drug complexes are stable, with minor structural arrangements and stable binding patterns. The PCA and FEL analysis also confirmed the structural stability of the complexes. Overall, these drugs displayed promising results as Eis inhibitors, that can be regarded as suitable candidates for experimental validation.

PMID:40051485 | PMC:PMC11880469 | DOI:10.1007/s40203-025-00325-5

Cancer Cell Int. 2025 Mar 6;25(1):79. doi: 10.1186/s12935-025-03712-2.

ABSTRACT

BACKGROUND: Colorectal cancer (CRC) poses a significant clinical challenge because of drug resistance, which can adversely impact patient outcomes. Recent research has shown that abnormalities within the tumor microenvironment, especially hyperglycemia, play a crucial role in promoting metastasis and chemoresistance, and thereby determine the overall prognosis of patients with advanced CRC.

METHODS: This study employs data mining and consensus molecular subtype (CMS) techniques to identify pitavastatin and atorvastatin as potential agents for targeting high glucose-induced drug resistance in advanced CRC cells. CRC cells maintained under either low or high glucose conditions were established and utilized to assess the cytotoxic effects of pitavastatin and atorvastatin, both with and without 5-fluorouracil (5-FU). CRC 3D spheroids cultured were also included to demonstrate the anti-drug resistance of pitavastatin and atorvastatin.

RESULTS: A bioinformatics analysis identified pitavastatin and atorvastatin as promising drug candidates. The CMS4 CRC cell line SW480 (SW480-HG) was established and cultured under high glucose conditions to simulate hyperglycemia-induced drug resistance and metastasis in CRC patients. Pitavastatin and atorvastatin could inhibit cell proliferation and 3D spheroid formation of CMS4 CRC cells under high glucose conditions. In addition, both pitavastatin and atorvastatin can synergistically promote the 5-FU-mediated cytotoxic effect and inhibit the growth of 5-FU-resistant CRC cells. Mechanistically, pitavastatin and atorvastatin can induce apoptosis and synergistically promote the 5-FU-mediated cytotoxic effect by activating autophagy, as well as the PERK/ATF4/CHOP signaling pathway while decreasing YAP expression.

CONCLUSION: This study highlights the biomarker-guided precision medicine strategy for drug repurposing. Pitavastatin and atorvastatin could be used to assist in the treatment of advanced CRC, particularly with CMS4 subtype CRC patients who also suffer from hyperglycemia. Pitavastatin, with an achievable dosage used for clinical interventions, is highly recommended for a novel CRC therapeutic strategy.

PMID:40050889 | DOI:10.1186/s12935-025-03712-2

BMC Cancer. 2025 Mar 6;25(1):412. doi: 10.1186/s12885-025-13733-9.

ABSTRACT

BACKGROUND: Targeting mitochondrial dynamics offers promising strategies for treating glioblastoma multiforme. Celastrol has demonstrated therapeutic effects on various cancers, but its impact on mitochondrial dynamics in glioblastoma multiforme remains largely unknown. We studied the effects of Celastrol on mitochondrial dynamics, redox homeostasis, and the proliferation.

METHODS: Mito-Tracker Green staining was conducted on U251, LN229, and U87-MG cells to evaluate the effects of Celastrol on mitochondrial dynamics. The Western blot analysis quantified the expression levels of mitochondrial dynamin, antioxidant enzymes, and cell cycle-related proteins. JC-1 staining was performed to discern mitochondrial membrane potential. Mitochondrial reactive oxygen species were identified using MitoSOX. The proliferative capacity of cells was assessed using Cell Counting Kit-8 analysis, and colony formation assays. Survival analysis was employed to evaluate the therapeutic efficacy of Celastrol in C57BL/6J mice with glioblastoma.

RESULTS: Our findings suggest that Celastrol (1 and 1.5 µM) promotes mitochondrial fission by downregulating the expression of mitofusin-1. A decrease in mitochondrial membrane potential at 1 and 1.5 µM indicates that Celastrol impaired mitochondrial function. Concurrently, an increase in mitochondrial reactive oxygen species and impaired upregulation of antioxidant enzymes were noted at 1.5 µM, indicating that Celastrol led to an imbalance in mitochondrial redox homeostasis. At both 1 and 1.5 µM, cell proliferation was inhibited, which may be related to the decreased expression levels of Cyclin-dependent kinase 1 and Cyclin B1. Celastrol extended the survival of GBM-afflicted mice.

CONCLUSION: Celastrol promotes mitochondrial fission in glioblastoma multiforme cells by reducing mitofusin-1 expression, accompanying mitochondrial dysfunction, lower mitochondrial membrane potential, heightened oxidative stress, and decreased Cyclin-dependent kinase 1 and Cyclin B1 levels. This indicates that Celastrol possesses potential for repurposing as an agent targeting mitochondrial dynamics in glioblastoma multiforme, warranting further investigation.

PMID:40050778 | DOI:10.1186/s12885-025-13733-9

Sci Rep. 2025 Mar 6;15(1):7840. doi: 10.1038/s41598-025-91757-8.

ABSTRACT

Drug repositioning is a transformative approach in drug discovery, offering a pathway to repurpose existing drugs for new therapeutic uses. In this study, we introduce the IDDNMTF model designed to predict drug repositioning opportunities with greater precision. The IDDNMTF model integrates multiple datasets, allowing for a more comprehensive analysis of drug-disease associations. We evaluated the IDDNMTF model using various combinations of datasets and found that its performance, as measured by AUC, AUPR, and F1 scores, improved with the inclusion of more data. This trend underscores the importance of data diversity in strengthening predictive capabilities. Comparatively, the IDDNMTF model demonstrated superior performance against the NMF model, solidifying its potential in drug repositioning. In summary, the IDDNMTF model offers a promising tool for identifying new therapeutic uses for existing drugs. Its predictive accuracy and interpretability are poised to accelerate the transition from bench to bedside, contributing to personalized medicine and the development of targeted treatments.

PMID:40050702 | DOI:10.1038/s41598-025-91757-8

Eur J Pharmacol. 2025 Mar 4:177461. doi: 10.1016/j.ejphar.2025.177461. Online ahead of print.

ABSTRACT

INTRODUCTION: & Aim: Novel treatments for idiopathic pulmonary fibrosis (IPF) are needed urgently. A better understanding of the molecular pathways activated by TGFβ1 in human lung tissue may facilitate the development of more effective anti-fibrotic medications. This study utilized proteomic analysis to test the hypothesis that TGFβ1 induces pro-fibrotic effects on human lung parenchyma proteome, and to evaluate the viability of this model for testing novel therapeutic targets.

METHODS: Non-fibrotic human lung parenchymal tissue from 11 patients was cultured for 7 days in serum-free (SF) media supplemented with TGFβ1 (10 ng/mL) or vehicle control, and the putative antifibrotic KCa3.1 ion channel blocker senicapoc or vehicle control. The tissue was homogenized, digested for bottom-up proteomics, and analysed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Principal component analysis, differential expression analysis, pathway analysis, and drug repurposing analysis were performed.

RESULTS: TGFβ1 stimulation for 7 days induced a strong fibrotic protein response relevant to IPF pathology. A total of 2,391 proteins were quantified, 306 upregulated and 285 downregulated (FDR-adjusted p-value<0.05). Of these, 118 were upregulated and 28 downregulated at log2(FC)>0.58. These changes were attenuated by senicapoc (100 nM). Drug repurposing analysis identified 265 drugs predicted to inhibit the effects of TGFβ1 in this model. These included clotrimazole, a KCa3.1 blocker, and nintedanib, a drug licenced for the treatment of IPF, providing validation of this approach.

CONCLUSION: A pro-fibrotic proteome is induced in human lung parenchyma exposed to TGFβ1, sensitive to pharmacological intervention. This approach has the potential to enhance therapeutic drug screening for IPF treatment.

PMID:40049575 | DOI:10.1016/j.ejphar.2025.177461

Adv Sci (Weinh). 2025 Mar 6:e2411325. doi: 10.1002/advs.202411325. Online ahead of print.

ABSTRACT

Drug repurposing identifies new therapeutic uses for the existing drugs originally developed for different indications, aiming at capitalizing on the established safety and efficacy profiles of known drugs. Thus, it is beneficial to bypass of early stages of drug development, and to reduction of the time and cost associated with bringing new therapies to market. Traditional experimental methods are often time-consuming and expensive, making artificial intelligence (AI) a promising alternative due to its lower cost, computational advantages, and ability to uncover hidden patterns. This review focuses on the availability of AI algorithms in drug development, and their positive and specific roles in revealing repurposing of the existing drugs, especially being integrated with virtual screening. It is shown that the existing AI algorithms excel at analyzing large-scale datasets, identifying the complicated patterns of drug responses from these datasets, and making predictions for potential drug repurposing. Building on these insights, challenges remain in developing efficient AI algorithms and future research, including integrating drug-related data across databases for better repurposing, enhancing AI computational efficiency, and advancing personalized medicine.

PMID:40047357 | DOI:10.1002/advs.202411325

Front Pharmacol. 2025 Feb 19;16:1519066. doi: 10.3389/fphar.2025.1519066. eCollection 2025.

ABSTRACT

BACKGROUND: Considering the role PARPs play in inflammation, we assessed the effect of PARP inhibition in an inflammatory skin condition, psoriasis, to explore novel avenues for the potential repurposing of PARP inhibitors that are currently used in tumour therapy.

METHODS: The imiquimod (IMQ)-induced model of psoriasis was applied in BALB/c mice. Mice received daily intraperitoneal injection of either one of four PARP inhibitors or their vehicle prior to treatment of the shaved back skin of mice with IMQ-containing cream or control cream for four days. The appearance of the skin of mice was scored daily according to the extent of erythema, induration and scaling. The most effective PARP inhibitor was selected for detailed studies on mouse skin and in a human keratinocyte cell line.

RESULTS: Of the PARP inhibitors, talazoparib and rucaparib improved the imiquimod-induced symptoms on mouse skin. Application of talazoparib in the psoriasis model resulted in maintained terminal differentiation and reduced proliferation of epidermal keratinocytes. Conversely, talazoparib also enhanced the production of pro-inflammatory chemokines in the skin of mice. These effects of talazoparib was associated with increased mitochondrial production of reactive oxygen species and a consequent activation of pro-apoptotic and pro-inflammatory pathways in keratinocytes.

CONCLUSION: PARP inhibition by talazoparib promotes terminal differentiation of epidermal keratinocytes that may be beneficial in psoriasis. Despite the fact that talazoparib exerted a pro-inflammatory effect in the skin, which is not unprecedented in anti-psoriatic therapy, these findings may advance the conduction of pre-clinical and clinical trials with PARP inhibitors in psoriasis management.

PMID:40046735 | PMC:PMC11879949 | DOI:10.3389/fphar.2025.1519066