Mol Divers. 2025 Mar 14. doi: 10.1007/s11030-025-11162-1. Online ahead of print.

ABSTRACT

Telomerase, a reverse transcriptase implicated in replicative immortality of cancers, remains a challenging target for therapeutic intervention due to its structural complexity and the absence of clinically approved small-molecule inhibitors. In this study, we explored drug repurposing as a pragmatic approach to address this gap, leveraging FDA-approved drugs to accelerate the identification of potential telomerase inhibitors. Using a structure-based drug discovery framework, we screened the DrugBank database through a previously validated pharmacophore model for the FVYL pocket in the hTERT thumb domain, the established binding site of BIBR1532. This was followed by molecular docking, pharmacokinetic filtering, and molecular dynamics (MD) simulations to evaluate the stability of protein-ligand complexes. Binding free energy calculations (MM-PBSA and MM-GBSA) were employed for cross-validation, identifying five promising candidates. Experimental validation using the Telomerase Repeat Amplification Protocol (TRAP) assay confirmed the inhibitory potential of Raltitrexed, showing significant inhibition with IC50 8.899 µM in comparison to control. Decomposition analysis and Structure-Activity Relationship (SAR) studies further offered insights into the binding mechanism, reinforcing the utility of the FVYL pocket as a druggable site. Raltitrexed's dual mechanism of action, targeting both telomerase and thymidylate synthase, underscores its potential as a versatile anticancer agent, suitable for combination therapies or standalone treatment. As the top lead, Raltitrexed demonstrates the potential of repurposed drugs in telomerase-targeted therapies, offering a time and cost-effective strategy for advancing its clinical development. The study also provides a robust framework for future drug development, addressing challenges in targeting telomerase for anticancer therapy.

PMID:40087255 | DOI:10.1007/s11030-025-11162-1

Mol Genet Metab. 2025 Mar 1;144(4):109073. doi: 10.1016/j.ymgme.2025.109073. Online ahead of print.

ABSTRACT

Rare diseases affect over 400 million people worldwide, with approved treatment available for less than 6 % of these diseases. Drug repurposing is a key strategy in the development of therapies for rare disease patients with large unmet medical needs. The process of repurposing drugs compared to novel drug development is a time-saving and cost-efficient method potentially resulting in higher success rates. To accelerate and ensure sustainability in therapy development for rare neurometabolic, neurological, and neuromuscular diseases, an international consortium SIMilarities in clinical and molecular PATHology (SIMPATHIC) has been established where we move away from the one drug one disease concept and move towards one drug targeting a pathomechanism shared between diseases, by applying parallel preclinical and clinical drug development. Here the consortium describes accelerators of drug repurposing pursued by the consortium, including 1) co-creation, 2) patient empowerment, 3) use of standardized induced pluripotent stem cell (iPSC)-derived disease models and cellular and molecular profiling, 4) high-throughput drug screening in neurons, 5) innovative clinical trial design, and 6) selection of appropriate exploitation and patient access models. In this way, a fast and effective drug repurposing pathway for several rare diseases will be established to reduce time from discovery to patient access.

PMID:40086177 | DOI:10.1016/j.ymgme.2025.109073

Drug Discov Today. 2025 Mar 11:104327. doi: 10.1016/j.drudis.2025.104327. Online ahead of print.

ABSTRACT

Rheumatoid arthritis (RA) presents a significant challenge in clinical management because of the dearth of effective drugs despite advances in understanding its mechanisms. Drug repurposing has emerged as a promising strategy to address this gap, offering potential cost savings and expediting drug discovery. Notably, computational methods, particularly machine learning (ML), have shown promise in RA drug repurposing. In this review, we survey various drug-repurposing approaches, both classical and contemporary, highlighting the pivotal role of ML. We summarize RA candidate drugs identified through computational strategies and discuss prevailing challenges in this domain. Leveraging ML, alongside a deepening understanding of RA mechanisms, holds promise for enhancing pharmacological treatment options for patients with RA.

PMID:40081521 | DOI:10.1016/j.drudis.2025.104327

Int J Mol Sci. 2025 Feb 28;26(5):2195. doi: 10.3390/ijms26052195.

ABSTRACT

Sphingolipidoses, a subgroup of lysosomal storage diseases (LSDs), are rare and debilitating disorders caused by defects in sphingolipid metabolism. Despite advancements in treatment, therapeutic options remain limited. Miglustat, a glucosylceramide synthase EC 2.4.1.80 (GCS) inhibitor, is one of the few available pharmacological treatments; however, it is associated with significant adverse effects that impact patients' quality of life. Drug repurposing offers a promising strategy to identify new therapeutic agents from approved drugs, expanding treatment options for rare diseases with limited therapeutic alternatives. This study aims to identify potential alternative inhibitors of GCS through a drug-repurposing approach, using computational and experimental methods to assess their therapeutic potential for sphingolipidoses. A library of approved drugs was screened using advanced computational techniques, including molecular docking, molecular dynamics simulations, and metadynamics, to identify potential GCS inhibitors. Promising candidates were selected for further in vitro validation to evaluate their inhibitory activity and potential as therapeutic alternatives to Miglustat. Computational screening identified several potential GCS inhibitors, with Dapagliflozin emerging as the most promising candidate. Experimental validation confirmed its efficacy, revealing a complementary mechanism of action to Miglustat while potentially offering a more favorable side effect profile. This study underscores the utility of computational and experimental methodologies in drug repurposing for rare diseases. The identification of Dapagliflozin as a potential GCS inhibitor provides a foundation for further preclinical and clinical evaluation, supporting its potential application in the treatment of sphingolipidoses.

PMID:40076817 | DOI:10.3390/ijms26052195

Int J Mol Sci. 2025 Feb 23;26(5):1910. doi: 10.3390/ijms26051910.

ABSTRACT

Reductive stress (RS), characterized by excessive accumulation of reducing equivalents such as NADH and NADPH, is emerging as a key factor in metabolic disorders and cancer. While oxidative stress (OS) has been widely studied, RS and its complex interplay with endocrine regulation remain less understood. This review explores molecular circuits of bidirectional crosstalk between metabolic hormones and RS, focusing on their role in diabetes, obesity, cardiovascular diseases, and cancer. RS disrupts insulin secretion and signaling, exacerbates metabolic inflammation, and contributes to adipose tissue dysfunction, ultimately promoting insulin resistance. In cardiovascular diseases, RS alters vascular smooth muscle cell function and myocardial metabolism, influencing ischemia-reperfusion injury outcomes. In cancer, RS plays a dual role: it enhances tumor survival by buffering OS and promoting metabolic reprogramming, yet excessive RS can trigger proteotoxicity and mitochondrial dysfunction, leading to apoptosis. Recent studies have identified RS-targeting strategies, including redox-modulating therapies, nanomedicine, and drug repurposing, offering potential for novel treatments. However, challenges remain, particularly in distinguishing physiological RS from pathological conditions and in overcoming therapy-induced resistance. Future research should focus on developing selective RS biomarkers, optimizing therapeutic interventions, and exploring the role of RS in immune and endocrine regulation.

PMID:40076537 | DOI:10.3390/ijms26051910

Molecules. 2025 Feb 24;30(5):1031. doi: 10.3390/molecules30051031.

ABSTRACT

Our research group aimed for the optimization of pharmacologic ascorbate (Ph-Asc)-induced cancer cell death. To reduce the required time and resources needed for development, an in silico system biological approach, an already approved medication, and a mild bioactive compound were used in our previous studies. It was revealed that both Ph-Asc and resveratrol (RES) caused DSBs in the DNA, and chloroquine (CQ) treatment amplified the cytotoxic effect of both Ph-Asc and RES in an autophagy independent way. In the present study, we aimed at the further clarification of the cytotoxic mechanism of Ph-Asc, CQ, and RES by comparing their DNA damaging abilities, effects on the cells' bioenergetic status, ROS, and lipid ROS generation abilities with those of the three currently investigated compounds (menadione, RSL3, H2O2). It could be assessed that the induction of DSBs is certainly a common point of their mechanism of action; furthermore, the observed cancer cell death due to the investigated treatments are independent of the bioenergetic status. Contrary to other investigated compounds, the DNA damaging effect of CQ seemed to be ROS independent. Surprisingly, the well-known ferroptosis inducer RSL3 was unable to induce lipid peroxidation in the pancreas ductal adenocarcinoma (PDAC) Mia PaCa-2 cell line. At the same time, it induced DSBs in the DNA, and the RSL3-induced cell death could not be suspended by the well-known ferroptosis inhibitors. All these observations suggest the ferroptosis resistance of this cell line. The observed DNA damaging effect of RSL3 definitely creates a new perspective in anticancer research.

PMID:40076255 | DOI:10.3390/molecules30051031

Cancers (Basel). 2025 Mar 6;17(5):903. doi: 10.3390/cancers17050903.

ABSTRACT

Background/Objectives: The molecular heterogeneity and metabolic flexibility of Hepatocellular Carcinoma (HCC) pose significant challenges to the efficacy of systemic therapy for advanced cases. Early screening difficulties often delay diagnosis, leading to more advanced stages at presentation. Combined with the inconsistent responses to current systemic therapies, HCC continues to have one of the highest mortality rates among cancers. Thus, this paper seeks to contribute to the development of systemic therapy options through the consideration of HCC's metabolic vulnerabilities and lay the groundwork for future in vitro studies. Methods: Transcriptomic data were used to calculate single and double knockout options for HCC using genetic Minimal Cut Sets. Furthermore, using QSAR modeling, drug repositioning opportunities were assessed to inhibit the selected genes. Results: Two single knockout options that were also annotated as essential pairs were found within the pyrimidine metabolism pathway of HCC, wherein the knockout of either DHODH or TYMS is potentially disruptive to proliferation. The result of the flux balance analysis and gene knockout simulation indicated a significant decrease in biomass production. Three machine learning algorithms were assessed for their performance in predicting the pIC50 of a given compound for the selected genes. SVM-rbf performed the best on unseen data achieving an R2 of 0.82 for DHODH and 0.81 for TYMS. For DHODH, the drugs Oteseconazole, Tipranavir, and Lusutrombopag were identified as potential inhibitors. For TYMS, the drugs Tadalafil, Dabigatran, Baloxavir Marboxil, and Candesartan Cilexetil showed promise as inhibitors. Conclusions: Overall, this study suggests in vitro testing of the identified drugs to assess their capabilities in inducing pyrimidine starvation on HCC.

PMID:40075750 | DOI:10.3390/cancers17050903

Purinergic Signal. 2025 Mar 13. doi: 10.1007/s11302-025-10078-7. Online ahead of print.

ABSTRACT

Neuroblastoma is a pediatric tumor accounting for approximately 8% of childhood cancers and is associated with high mortality rates among children aged 1 to 5 years. Standard treatments often fall short, leading to recurrence and metastasis due to the development of chemoresistance. A promising approach to address this challenge involves targeting purinergic signaling pathways and drug repurposing. The combination of flubendazole in nanoformulation and vincristine exhibited synergistic effects in ACN cells, enhancing treatment efficacy. Vincristine combined with the P2X7 receptor antagonist Brilliant Blue-G showed antagonistic effects, and interactions between nanoFBZ and Brilliant Blue-G were dose-dependent. Furthermore, ACN cells exposed to 213 nM of vincristine weekly for three weeks resulted in vincristine-resistant cells with significantly higher resistance (IC50 approximately 300 times greater) compared to parental cells. P2Y2 receptor expression was augmented in vincristine-resistant cells, particularly after treatment with nanoFBZ and Brilliant Blue-G, while adenosine A1, A2B, and P2Y6 receptor expression levels decreased. P2X7 receptor expression was also reduced in vincristine-resistant cells treated with nanoFBZ. P2X7 receptor agonism and P2Y2 receptor blockade slightly elevated resistance. In conclusion, this study suggests that combining nanoFBZ with vincristine chemotherapy may offer a promising strategy for improving the treatment efficacy of neuroblastoma. The synergy between nanoFBZ and vincristine enhanced therapeutic outcomes, and P2X7 receptor antagonism further reduced neuroblastoma cell viability.

PMID:40075009 | DOI:10.1007/s11302-025-10078-7

Sci Rep. 2025 Mar 12;15(1):8518. doi: 10.1038/s41598-024-83633-8.

ABSTRACT

Although the SARS-CoV-2 epidemic worldwide has gradually decreased, in some areas, the situation has not yet been stamped and has become a global health emergency. It is quite possible that we could again be threatened by a new coronavirus. Therefore, new nucleotide analog drugs and vaccines or using drug repositioning for SARS-CoV-2 still has been developed, yet their safety and efficacy against COVID-19 remains underexplored. Malabaricone C is 2,6-dihydroxyphenyl acylphenol found in edible plants such as the mace spice of nutmeg derived from the seeds of Myristica fragrans. In this study, we identified malabaricone C as the first inhibitor of SARS-CoV-2 from natural food with a safe alternative for drugs. Malabaricone C and its chemical derivatives showed EC50 values of 1-1.5 μM against SARS-CoV-2 (WK-521, ancestral strain) and its variant strains in mammalian cells (HEK293T and Vero E6). In addition, we have successfully established novel evaluation system for the inhibition of SARS virus cell fusion by visualization for providing a versatile tool for study SARS-CoV-2 mediated fusion. Furthermore, our experiments suggested that malabaricone C could affect the distribution of sphingomyelin on the plasma membrane, which involves in viral infections. Thus, in light of the beneficial effect of malabaricone C on viral infection, the nontoxic malabaricone C is a suitable candidate as a drug that can be employed in the treatment and prevention of COVID-19. Moreover, it may potentially be used to treat acute infections of other enveloped viruses.

PMID:40074774 | DOI:10.1038/s41598-024-83633-8

Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2024 Oct 28;49(10):1601-1610. doi: 10.11817/j.issn.1672-7347.2024.240109.

ABSTRACT

OBJECTIVES: Staphylococcus epidermidis (S. epidermidis) adheres to the surface of medical devices, forming highly drug-resistant biofilms, which has made the development of novel antibacterial agents against S. epidermidis and its biofilms a key research focus. By drug repurposing, this study aims to explore the combinational antimicrobial effects between pinaverium bromide (PVB), a L-type calcium channel blocker, and oxacillin (OXA) against S. epidermidis.

METHODS: Clinical isolates of S. epidermidis were collected from January to September 2022 at the Department of Clinical Laboratory of the Third Xiangya Hospital, Central South University. The minimal inhibitory concentrations (MICs) of PVB and OXA were determined using the broth microdilution method. Checkerboard assays and time-kill curves were performed to assess the fractional inhibitory concentration index and synergistic bactericidal efficiency of the drug combination. Resistance selection assays evaluated PVB's ability to inhibit the development of OXA resistance. Biofilm eradication assays, combined with confocal laser scanning microscopy (CLSM) and the persister cell quantification, were conducted to evaluate the effect of PVB and OXA on drug-resistant biofilms and persister cells. The mechanisms of PVB action were further investigated using transmission electronic microscopy (TEM), reactive oxygen species (ROS) quantification, and ATP quantification.

RESULTS: The MICs of PVB and OXA against the standard strain S. epidermidis RP62A were both 8 μg/mL. Checkerboard assays showed that the fractional inhibitory concentration index (FICI) for the combination was 0.250 0 for RP62A and ranged from 0.187 5 to 0.500 0 for clinical isolates, indicating synergistic effects. Resistance selection assays demonstrated that PVB not only failed to induce resistance but also effectively inhibited the development of OXA resistance. The combination of 1×MIC of PVB and OXA reduced biofilm biomass (A570 nm) from (2.36±0.46) to (1.12±0.39) (t=3.504, P=0.02). CLSM revealed significant biofilm structural disruption and an increased proportion of dead bacteria. Additionally, after 4 hours of treatment, the total persister cell count was reduced from lg(7.73±0.21) to lg(2.79±0.43) (t=4.143, P=0.014). Synergistic biofilm eradication was further confirmed in clinical isolates. TEM revealed that PVB caused significant bacterial structural damage. The combination of OXA and PVB significantly induced ROS production, increasing the relative fluorescence intensity from (30 000.00±2 000.00) to (45 666.67±2 081.67) (t=10.68, P<0.001), and markedly reduced ATP generation, lowering the relative fluorescence intensity form (565.00±33.18) to (205.67±35.23) (t=4.932, P=0.003).

CONCLUSIONS: The combination of PVB and OXA exhibits significant synergistic antimicrobial activity against S. epidermidis, its biofilms, and persister cells. This combination holds promise as a potential alternative therapy for biofilm-associated infections caused by S. epidermidis.

PMID:40074309 | DOI:10.11817/j.issn.1672-7347.2024.240109

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