Neurobiol Dis. 2025 Apr 10:106909. doi: 10.1016/j.nbd.2025.106909. Online ahead of print.

ABSTRACT

BACKGROUND: Previous studies have shown significant sex differences in AD with regarding its epidemiology, pathophysiology, clinical presentation, and treatment response. However, the transcriptome variances associated with sex in AD remain unclear.

METHODS: RNA sequencing (RNA-seq) and transcriptomic analyses were performed on peripheral blood samples from total of 54 patients, including male AD patients (n = 15), female AD patients (n = 10), male MCI patients (n = 7), female MCI patients (n = 11), male healthy controls (n = 6), female healthy controls (n = 5). The snRNA-seq dataset (GSE167494, GSE157827) of prefrontal cortex tissues was obtained from the Gene Expression Omnibus (GEO). We conducted an investigation into differentially expressed genes and pathways in the peripheral blood cells as well as prefrontal cortex tissues of both male and female AD patients with consideration to sex-related factors. Additionally, we analyzed the distribution and characteristics of cells in the cerebral cortex as well as the interaction and communication between cells of male and female AD patients. Connectivity Map (CMap) was utilized for predicting and screening potential sex-specific drugs for AD.

RESULTS: The transcriptome profile and associated biological processes in the peripheral blood of male and female AD and MCI patients exhibit discernible differences, including upregulation of BASP1 in AD male patients and arousing TNS1 in AD female patients. The distribution of various cell types in the prefrontal cortex tissues differs between male and female AD patients, like neuron and oligodendrocyte decreased and endothelial cell and astrocyte increased in female compared with male, while a multitude of genes exhibit significant differential expression. The results of cell communication analysis, such as collagen signaling pathway, suggest that sex disparities impact intercellular interactions within prefrontal cortex tissues among individuals with AD. By drug repositioning, several drugs, including torin-2 and YM-298198, might have the potential to therapeutic value of MCI or AD, while drugs like homoharringtonine and teniposide have potential opposite effects in different sexes.

CONCLUSION: The characteristics of the transcriptome in peripheral blood and single-cell transcriptome in the prefrontal cortex exhibit significant differences between male and female patients with AD, which providing a basis for future sex stratified treatment of AD.

PMID:40220916 | DOI:10.1016/j.nbd.2025.106909

Int Immunopharmacol. 2025 Apr 11;155:114622. doi: 10.1016/j.intimp.2025.114622. Online ahead of print.

ABSTRACT

The lysosomal cysteine protease cathepsin S supports host defence by promoting the maturation of MHC class-II proteins. In contrast, increased cathepsin S activity mediates tissue destructive immune responses in autoimmune and inflammatory diseases. Therefore, cathepsin S is a key target in drug discovery programs. Here, we critically reviewed the specific mechanisms by which cathepsin S mediates autoimmune and hyperinflammatory responses to identify new targets for therapeutic immunomodulation. To this end, we performed literature review utilizing PubMed, drug database of US FDA, European Medicines Agency and the Drug-Gene Interaction Database. Cathepsin S destroys T cell epitopes and reduces endogenous antigen diversity, impairing negative selection of autoreactive T cells that could recognize these epitopes. Moreover, cathepsin S critically regulates inflammatory disease severity by generating proinflammatory molecules (PAR-1, PAR-2, IL-36γ, Fractalkine, Endostatin, Ephrin-B2), inactivating anti-inflammatory mediators (SLPI) and degrading molecules involved in antimicrobial and immunomodulatory responses (surfactant protein-A, LL-37, beta-defensins), inter-endothelial/-epithelial barrier function, gene repair and energy homeostasis. These pathways could be targeted by repositioning of existing drugs. These findings suggest that inhibiting cathepsin S or a specific downstream target of cathepsin S by repositioning of existing drugs could be a promising strategy for treating autoimmune and inflammatory diseases. Current cathepsin S inhibitors in clinical trials face challenges, highlighting the need for innovative inhibitors that function effectively in various cellular compartments with differing pH levels, without targeting the shared catalytic site of cysteine cathepsins.

PMID:40220622 | DOI:10.1016/j.intimp.2025.114622

NPJ Antimicrob Resist. 2025 Apr 11;3(1):25. doi: 10.1038/s44259-025-00097-0.

ABSTRACT

Slow- and non-growing bacterial populations, along with intracellular pathogens, often evade standard antibacterial treatments and are linked to persistent and recurrent infections. This necessitates the development of therapies specifically targeting nonproliferating bacteria. To identify compounds active against non-growing uropathogenic Escherichia coli (UPEC) we performed a drug-repurposing screen of 6454 approved drugs and drug candidates. Using dilution-regrowth assays, we identified 39 compounds that either kill non-growing UPEC or delay its regrowth post-treatment. The hits include fluoroquinolones, macrolides, rifamycins, biguanide disinfectants, a pleuromutilin, and anti-cancer agents. Twenty-nine of the hits have not previously been recognized as active against non-growing bacteria. The hits were further tested against non-growing Pseudomonas aeruginosa and Staphylococcus aureus. Ten compounds - solithromycin, rifabutin, mitomycin C, and seven fluoroquinolones-have strong bactericidal activity against non-growing P. aeruginosa, killing >4 log10 of bacteria at 2.5 µM. Solithromycin, valnemulin, evofosfamide, and satraplatin are unique in their ability to selectively target non-growing bacteria, exhibiting poor efficacy against growing bacteria. Finally, 31 hit compounds inhibit the growth of intracellular Shigella flexneri in a human enterocyte infection model, indicating their ability to permeate the cytoplasm of host cells. The identified compounds hold potential for treating persistent infections, warranting further comparative studies with current standard-of-care antibiotics.

PMID:40216902 | DOI:10.1038/s44259-025-00097-0

Exp Cell Res. 2025 Apr 9:114551. doi: 10.1016/j.yexcr.2025.114551. Online ahead of print.

ABSTRACT

Due to the expensive and lengthy process of drug design and approval, drug repurposing (or repositioning) has become another option for identifying preexisting molecules that may be used for alternative purposes. Recently, some antimalarial compounds have been shown to display efficacy against cancer cell proliferation. In this study, we provide evidence to suggest that multiple preexisting antimalarial drugs can reduce the viability of human cancer cells in culture. Furthermore, we provide the first evidence that one antimalarial, Tafenoquine (LD50=9.6μM in HCT116 cells), is capable of decreasing viability with an efficacy comparable to Etoposide (LD50=15.2μM in HCT116 cells) Further, Tafenoquine induces apoptosis and increases the expression of genes involved in cell cycle arrest and cell death. We also show that cells are sensitized to the apoptotic effects of Tafenoquine following depletion of the heme oxygenase 1 (HMOX-1) gene. Collectively, our studies confirm that antimalarial compounds hold the potential for use as anticancer agents and provide the first evidence to detail the potent efficacy of Tafenoquine against cancer cells in culture.

PMID:40216009 | DOI:10.1016/j.yexcr.2025.114551

Biomed Pharmacother. 2025 Apr 10;186:118031. doi: 10.1016/j.biopha.2025.118031. Online ahead of print.

ABSTRACT

The coagulation system plays a complex role in cancer therapy. Endothelial damage and tissue factor increased by chemotherapy initiate the coagulation cascade, producing active FXa and releasing thrombin. Thrombin triggers tumor growth and metastasis, leading to severe thromboembolic events in cancer patients. Direct thrombin inhibitors do not have the expected anti-metastatic effect as PAR-2 remains active and increases the risk of bleeding. Therefore, dual inhibition of thrombin by FXa inhibition and plasmin inhibition, which converts fibrin to fibrinogen, is targeted. Clinical studies show that the use of tranexamic acid in patients on NOAC therapy may be beneficial without increasing the risk of bleeding. This approach offers a promising strategy to provide an anti-metastatic effect in cancer treatment.

PMID:40215647 | DOI:10.1016/j.biopha.2025.118031

Cells. 2025 Apr 2;14(7):533. doi: 10.3390/cells14070533.

ABSTRACT

Failure in the proliferation, recruitment, mobilization, and/or differentiation of oligodendrocyte precursor cells (OPCs) impedes remyelination in central nervous system (CNS) demyelinating diseases. Our group has recently achieved the generation of functional oligodendroglia through direct lineage conversion by expressing Sox10, Olig2, and Zfp536 genes in adult rat adipose tissue-derived stromal cells. The present study aimed to determine whether various repurposed drugs or molecules could enhance the myelinating capacities of these induced OPCs (iOPCs). We report that kainate, benztropine, miconazole, clobetasol, and baclofen promote in vitro iOPCs migration, differentiation, and ensheathing abilities through mechanisms similar to those observed in rat neural stem cell-derived OPCs. This research supports the potential use of iOPCs as they provide an alternative and reliable cell source for testing the effects of in vitro promyelinating repurposed drugs and for assessing the molecular and cellular mechanisms involved in therapeutic strategies for demyelinating diseases.

PMID:40214487 | DOI:10.3390/cells14070533

Ann Med Surg (Lond). 2025 Feb 28;87(3):1506-1528. doi: 10.1097/MS9.0000000000003043. eCollection 2025 Mar.

ABSTRACT

Cancer is one of the leading causes of death worldwide. In cancer therapy, anti-cancer drugs are the current treatment-of-choice for patients with metastatic cancers, but these drugs present a major drawback: they destroy healthy cells along with cancerous cells. Unfortunately, the drug discovery process for de novo drugs is costly and time-consuming. To address this global problem, our research team has established the concept of "Chemotherapy with a molecular rational basis", which focuses on the identification of molecular targets in tumor cells, whose activation or inhibition induces apoptosis or sensitizes the tumor cells to apoptosis. Here we review the experimental and clinical evidence of pentoxifylline (PTX) in the setting of chemotherapy with a molecular rational basis. A search of the literature was conducted for articles published during the period from 2 January 2003 to 21 October 2024. Articles published in English or Spanish were included. The keywords "Pentoxifylline" OR "BL 191" OR "trental" AND "cancer" were used for in vitro, in vivo, and clinical studies. PTX is an approved, accessible, and relatively safe drug. Furthermore there is a large body of experimental and clinical evidence of the beneficial effects of PTX in cancer therapy, either alone or in combination with antitumor drugs, sometimes even more effective than traditional chemotherapy regimens. However, it is necessary to carry out larger clinical trials in cancer patients to identify the benefits, adverse effects and even pharmacological interactions of PTX with current chemotherapy regimens and thus achieve a new drug repositioning that benefits our patients.

PMID:40213176 | PMC:PMC11981314 | DOI:10.1097/MS9.0000000000003043

Eur J Med Res. 2025 Apr 11;30(1):267. doi: 10.1186/s40001-025-02443-4.

ABSTRACT

Current TB treatment regimens are hindered by drug resistance, numerous adverse effects, and long treatment durations, highlighting the need for 'me-better' treatment regimens. Host-directed therapy (HDT) has gained recognition as a promising approach in TB treatment. It allows the repurposing of existing drugs approved for other conditions and aims to enhance the effectiveness of existing anti-TB therapies, minimize drug resistance, decrease treatment duration, and adverse effects. By modulating the host immune response, HDT ameliorates immunopathological damage and improves overall outcomes by promoting autophagy, antimicrobial peptide production, and other mechanisms. It holds promise for addressing the challenges posed by multiple and extensively drug-resistant Mycobacterium tuberculosis strains, which are increasingly difficult to treat using conventional therapies. This article reviews various HDT candidates, including repurposed drugs, explores their underlying mechanisms such as autophagy promotion and inflammation reduction, while emphasizing their potential to improve TB treatment outcomes and outlining future research directions.

PMID:40211397 | DOI:10.1186/s40001-025-02443-4

Cell Commun Signal. 2025 Apr 10;23(1):179. doi: 10.1186/s12964-025-02185-0.

ABSTRACT

BACKGROUND: About 40% of relapsed or non-responder tumors exhibit therapeutic resistance in the absence of a clear genetic cause, suggesting a pivotal role of intracellular communication. A deeper understanding of signaling pathways rewiring occurring in resistant cells is crucial to propose alternative effective strategies for cancer patients.

METHODS: To achieve this goal, we developed a novel multi-step strategy, which integrates high sensitive mass spectrometry-based phosphoproteomics with network-based analysis. This strategy builds context-specific networks recapitulating the signaling rewiring upon drug treatment in therapy-resistant and sensitive cells.

RESULTS: We applied this strategy to elucidate the BCR::ABL1-independent mechanisms that drive relapse upon therapy discontinuation in chronic myeloid leukemia (CML) patients. We built a signaling map, detailing - from receptor to key phenotypes - the molecular mechanisms implicated in the control of proliferation, DNA damage response and inflammation of therapy-resistant cells. In-depth analysis of this map uncovered novel therapeutic vulnerabilities. Functional validation in patient-derived leukemic stem cells revealed a crucial role of acquired FLT3-dependency and its underlying molecular mechanism.

CONCLUSIONS: In conclusion, our study presents a novel generally applicable strategy and the reposition of FLT3, one of the most frequently mutated drivers of acute leukemia, as a potential therapeutic target for CML relapsed patients.

PMID:40211380 | DOI:10.1186/s12964-025-02185-0

J Invest Dermatol. 2025 Apr 8:S0022-202X(25)00396-3. doi: 10.1016/j.jid.2025.03.029. Online ahead of print.

NO ABSTRACT

PMID:40210113 | DOI:10.1016/j.jid.2025.03.029

IEEE J Biomed Health Inform. 2025 Apr 10;PP. doi: 10.1109/JBHI.2025.3559570. Online ahead of print.

ABSTRACT

Drug repositioning, which identifies new therapeutic potential of approved drugs, is instrumental in accelerating drug discovery. Recently, to alleviate the effect of data sparsity on predicting possible drug-disease associations (DDAs), graph contrastive learning (GCL) has emerged as a promising paradigm for learning discriminative representations of drugs and diseases through distilling informative self-supervised signals. However, existing GCLbased methods devised for DDA prediction still encounter two limitations. Firstly, the crucial heterogeneous property, which allows for capturing nuanced interaction semantics between biological entities, is overlooked. The second is how to perform contrastive view augmentation without relying on stochastic perturbation. In this study, we propose a novel multi-view contrastive learning approach for DDA prediction, namely MICLE. To handle the first issue, proteinrelated bipartite graphs are integrated with the original DDA network in advance, thereby composing a heterogeneous biological network (HBN). Besides, heterogeneous graph neural network is applied to mine the rich connectivity patterns implicit in the above HBN. For the second limitation, we design the complementary inter-view and intra-view contrastive learning tasks. Specifically, the former ensures that the mutual information between paired nodes across views is maximized, the latter enhances the agreement between each node and its first-order neighbors on similarity networks. Extensive experiments conducted on three benchmarks under 10-fold cross-validation demonstrate the model effectiveness. Source code and datasets are available at https://github.com/OleCui/paper MICLE.

PMID:40208759 | DOI:10.1109/JBHI.2025.3559570

Biochem Biophys Rep. 2025 Mar 19;42:101957. doi: 10.1016/j.bbrep.2025.101957. eCollection 2025 Jun.

ABSTRACT

Colorectal cancer (CRC) is a multifaceted disease characterized by abnormal cell proliferation in the colon and rectum. The BCL-2 family proteins are implicated in CRC pathogenesis, yet the impacts of genetic variations within these proteins remains elusive. This in-silico study employs diverse sequence- and structure-based bioinformatics tools to identify potentially pathogenic nonsynonymous single nucleotide polymorphisms (nsSNPs) in BCL-2 family proteins. Leveraging computational tools including SIFT, PolyPhen-2, SNPs&GO, PhD-SNP, PANTHER, and Condel, 94 nsSNPs were predicted as deleterious, damaging, and disease-associated by at least five tools. Stability analysis with I-Mutant2.0, MutPred, and PredictSNP further identified 31 nsSNPs that reduce protein stability. Conservation analysis highlighted highly functional, exposed variants (rs960653284, rs758817904, rs1466732626, rs569276903, rs746711568, rs764437421, rs779690846, and rs2038330314) and structural, buried variants (rs376149674, rs1375767408, rs1582066443, rs367558446, rs367558446, rs1319541919, and rs1370070128). To explore the functional effects of these mutations, molecular docking and molecular dynamics simulations were conducted. G233D (rs376149674) and R12G (rs960653284) mutations in the BCL2 protein exhibited the greatest differences in docking scores with d-α-Tocopherol and Tocotrienol, suggesting enhanced protein-ligand interactions. The simulations revealed that d-α-Tocopherol and Tocotrienol (strong binders) contributed to greater stability of BCL-2 family proteins, while Fluorouracil, though weaker, still demonstrated selective binding stability. This work represents the first comprehensive computational analysis of functional nsSNPs in BCL-2 family proteins, providing insights into their roles in CRC pathogenesis. While these findings demand experimental validation, they hold great promise for guiding future large-scale population studies, facilitating drug repurposing efforts, and advancing the development of targeted diagnostic and therapeutic modalities for CRC.

PMID:40207085 | PMC:PMC11979393 | DOI:10.1016/j.bbrep.2025.101957

Front Cell Dev Biol. 2025 Mar 26;13:1505697. doi: 10.3389/fcell.2025.1505697. eCollection 2025.

ABSTRACT

BACKGROUND: Understanding the cell functionality during disease progression or drugs' mechanism are major challenges for precision medicine. Predictive models describing biological phenotypes can be challenging to obtain, particularly in scenarios where sample availability is limited, such as in the case of rare diseases. Here we propose a new method that reproduces the fibroadipogenic expansion that occurs in muscle wasting.

METHODS: We used immortalized fibroadipogenic progenitor cells (FAPs) and differentiated them into fibroblasts or adipocytes. The method successfully identified FAPs cell differentiation fate using accurate measurements of changes in specific proteins, which ultimately constitute a valid cellular in vitro platform for drug screening. Results were confirmed using primary FAPs differentiation as well as comparison with omics data from proteomics and genomic studies.

RESULTS: Our method allowed us to screen 508 different drugs from 2 compounds libraries. Out of these 508, we identified 4 compounds that reduced fibrogenesis and adipogenesis of ≥30% of fibrogenesis and adipogenesis using immortalized cells. After selecting the optimal dose of each compound, the inhibitory effect on FAP differentiation was confirmed by using primary FAPs from healthy subjects (n = 3) and DMD patients (n = 3). The final 4 selected hits reduced fibrogenic differentiation in healthy and DMD samples. The inhibition of adipogenesis was more evident in DMD samples than healthy samples. After creating an inhibitory map of the tested drugs, we validated the signalling pathways more involved in FAPs differentiation analysing data from proteomic and genomic studies.

CONCLUSION: We present a map of molecular targets of approved drugs that helps in predicting which therapeutic option may affect FAP differentiation. This method allows to study the potential effect of signalling circuits on FAP differentiation after drug treatment providing insights into molecular mechanism of action of muscle degeneration. The accuracy of the method is demonstrated by comparing the signal pathway activity obtained after drug treatment with proteomic and genomic data from patient-derived cells.

PMID:40206397 | PMC:PMC11979640 | DOI:10.3389/fcell.2025.1505697

OMICS. 2025 Apr 10. doi: 10.1089/omi.2024.0205. Online ahead of print.

ABSTRACT

The COVID-19 pandemic phase caused by the SARS-CoV-2 has ended, but the emergence of new variants continues to threaten public health. The public health toolbox for COVID-19 is in need of not only vaccines but also drug discovery against the SARS-CoV-2 virus, the causative agent for the ongoing COVID-19 infections. We report here an in silico molecular docking and dynamics study that uncovered the interactions of 26 flexible heteroarotinoids (FHT18), which are a class of anti-cancer compounds, as potential inhibitors against all 24 SARS-CoV-2 proteins. Of the 624 docked complexes, 69 displayed binding energies between -9.0 and -11.6 kcal/mol, indicating good to strong binding affinities. At least five of these compounds displayed excellent binding affinities against the nonstructural protein 2, papain-like protease, nonstructural protein 4 (Nsp4), proof-reading exoribonuclease, membrane protein, and nucleocapsid protein. Structure-activity relationship (SAR) analyses of these results revealed that a urea linker in place of a thiourea linker, enhanced the hydrophobic side chains attached to the chromane unit, and a CF3 or OCF3 functional group attached to the benzene ring contributed to increased binding affinities. Further, the molecular dynamics simulation study of the best-docked complex FHT18-6c with Nsp4 remained stable for at least 200 ns, leading to decreased structural fluctuations and increased compactness of the binding site. In conclusion, FHT18-6c deserves further translational research to explore its potential for repurposing as a potent drug candidate to combat COVID-19. We also call for continued drug discovery efforts to enrich the public health toolbox for COVID-19.

PMID:40205995 | DOI:10.1089/omi.2024.0205

Mol Biol Rep. 2025 Apr 9;52(1):373. doi: 10.1007/s11033-025-10474-7.

ABSTRACT

BACKGROUND: Gastric cancer is a highly heterogeneous and aggressive disease with limited treatment options, necessitating innovative therapeutic strategies. Drug repurposing, a cost-effective approach, offers opportunities to identify new applications for existing medications. This study systematically investigated the apoptotic effects of serotonergic drugs on MKN-45 gastric cancer cells, providing a novel perspective on serotonin signaling in cancer therapy.

METHODS AND RESULTS: MKN-45 cells were treated with concentrations of Tropisetron, Imipramine, Ketanserin, Citalopram, and Cyproheptadine. The IC50 values were determined using an MTT assay, while acridine orange/ethidium bromide staining and Annexin V/PI flow cytometry assessed apoptotic activity. Gene expression related to serotonin receptors (HTR2A, HTR2B, HTR3A), Serotonin transporter (SLC6A4), apoptosis (Bcl-2, Bax), and proliferation (PCNA) was evaluated via real-time PCR. Tropisetron, Imipramine, Ketanserin, and Cyproheptadine demonstrated statistically significant apoptotic induction compared to untreated cells. These treatments significantly reduced anti-apoptotic Bcl-2 and PCNA, proliferation marker, expression, while pro-apoptotic Bax expression was markedly elevated (p < 0.05).

CONCLUSIONS: This study highlights the potential of Tropisetron, Imipramine, Ketanserin, and Cyproheptadine as repurposed drugs for gastric cancer therapy, with Tropisetron and Imipramine showing particularly promising apoptotic effects. These findings pave the way for further preclinical and clinical investigations, offering a foundation for personalized therapeutic strategies in gastric cancer management.

PMID:40202572 | DOI:10.1007/s11033-025-10474-7

J Pharm Anal. 2025 Mar;15(3):101045. doi: 10.1016/j.jpha.2024.101045. Epub 2024 Jul 18.

ABSTRACT

Targeted covalent inhibitors, primarily targeting cysteine residues, have attracted great attention as potential drug candidates due to good potency and prolonged duration of action. However, their discovery is challenging. In this research, a database-assisted liquid chromatography-tandem mass spectrometry (LC-MS/MS) strategy was developed to quickly discover potential cysteine-targeting compounds. First, compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes. And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database. Second, substrate-independent product ions produced from N-acetyl-cysteine moiety were selected. Third, multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds. This strategy showed broad applicability, and covalent compounds with diverse structures were screened out, offering structural resources for covalent inhibitors development. Moreover, the screened compounds, norketamine and hydroxynorketamine, could modify synaptic transmission-related proteins in vivo, indicating their potential as covalent inhibitors. This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.

PMID:40201900 | PMC:PMC11978337 | DOI:10.1016/j.jpha.2024.101045

Bioinform Adv. 2025 Feb 18;5(1):vbaf029. doi: 10.1093/bioadv/vbaf029. eCollection 2025.

ABSTRACT

MOTIVATION: Understanding which genes are significantly affected by drugs is crucial for drug repurposing, as drugs targeting specific pathways in one disease might be effective in another with similar genetic profiles. By analyzing gene expression changes in cells before and after drug treatment, we can identify the genes most impacted by drugs.

RESULTS: The Biologically-Aware Interpretable Differential Gene Expression Ranking (BADGER) model is an interpretable model designed to predict gene expression changes resulting from interactions between cancer cell lines and chemical compounds. The model enhances explainability through integration of prior knowledge about drug targets via pathway information, handles novel cancer cell lines through similarity-based embedding, and employs three attention blocks that mimic the cascading effects of chemical compounds. This model overcomes previous limitations of cell line range and explainability constraints in drug-cell response studies. The model demonstrates superior performance over baselines in both unseen cell and unseen pair split evaluations, showing robust prediction capabilities for untested drug-cell line combinations.

AVAILABILITY AND IMPLEMENTATION: This makes it particularly valuable for drug repurposing scenarios, especially in developing therapeutic plans for new or resistant diseases by leveraging similarities with other diseases. All code and data used in this study are available at https://github.com/dmis-lab/BADGER.git.

PMID:40201234 | PMC:PMC11978390 | DOI:10.1093/bioadv/vbaf029

J Mol Graph Model. 2025 Apr 5;138:109036. doi: 10.1016/j.jmgm.2025.109036. Online ahead of print.

ABSTRACT

The effective treatment of neurological diseases, particularly Alzheimer's disease (AD), is a significant source of frustration for drug discovery scientists. The lengthy process of drug discovery further makes this task exceedingly challenging. To enable a rapid stride in drug discovery, we focused on the drug repurposing strategy to identify new N-methyl-D-aspartate receptor (NMDAR) inhibitors from the pool of 1827 approved USFDA drugs. The high throughput virtual screening (HTVS) followed by molecular docking and molecular mechanics studies enabled us to identify two drugs, Ertugliflozin (Dock Score: -9.43 kcal/mol, MMGBSA: -104.50 kcal/mol) and Selpercatinib (Dock Score: 8.11 kcal/mol, MMGBSA: 83.62 kcal/mol), with a high affinity towards the NMDAR. The molecular dynamics analysis on these identified drugs led us to choose Ertugliflozin for its better stability as a lead for further studies. The corroboration of in silico findings led us to deduce that Ertugliflozin can inhibit NMDAR with an IC50 of 613.19 nM. These results were confirmed by the anti-NMDAR ELISA-based analysis, which was further deduced via western blotting. The work is further supported by strong literature evidence that concludes the impact of antidiabetic molecules on AD progression, along with the evidence that Ertugliflozin possesses efficacy against AD with unequivocal evidence on the biological target and the mechanism. Further work, however, is required to establish this association in the in vivo or suitable model that could mimic the AD microenvironment as a part of future research.

PMID:40199086 | DOI:10.1016/j.jmgm.2025.109036

Am J Respir Cell Mol Biol. 2025 Apr 8. doi: 10.1165/rcmb.2024-0303OC. Online ahead of print.

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disease lacking effective treatment. Focusing on early COPD should help to discover disease modifying therapies. We examined the role of the CXCL12/CXCR4 axis in early COPD using human samples and murine models. Blood samples and lung tissues from both individuals with early COPD and controls were analyzed for CXCL12 and CXCR4 levels. To generate an early-like COPD model, 10-week-old male C57BL/6J mice were exposed to cigarette smoke (CS) for 10 weeks and intranasal instillations of polyinosinic-polycytidylic acid (poly(I:C)) for the last five weeks to mimic exacerbations. The number of cells expressing CXCR4 was increased in the blood of individuals with COPD, as well as in the blood of exposed mice. Lung CXCL12 expression was higher in both early COPD patients and exposed mice. Exposed mice presented mild airflow obstruction, peri-bronchial fibrosis, and right heart thickening. The density of fibrocyte-like cells expressing CXCR4 increased in the bronchial submucosa of these mice. Conditional inactivation of CXCR4 as well as pharmacological inhibition of CXCR4 with plerixafor injections improved lung function, reduced inflammation, and protected against CS and poly-(I:C)-induced airway and cardiac remodeling. CXCR4-/- and plerixafor-treated mice also had fewer CXCR4-expressing circulating cells and a lower density of peri-bronchial fibrocyte-like cells. We demonstrate that targeting CXCR4 has beneficial effects in an animal model mimicking early COPD. While these preclinical findings are encouraging, further research is needed to explore the potential for transferring these insights into clinical applications, including drug repurposing.

PMID:40198797 | DOI:10.1165/rcmb.2024-0303OC

Microbiol Spectr. 2025 Apr 8:e0233224. doi: 10.1128/spectrum.02332-24. Online ahead of print.

ABSTRACT

Tuberculosis remains the deadliest infectious disease of the 21st century. New antimicrobials are needed to improve treatment outcomes and enable therapy shortening. Drug repurposing is an alternative to the traditional drug discovery process. The avermectins are a family of macrocyclic lactones with anthelmintic activity active against Mycobacterium tuberculosis. However, their mode of action in mycobacteria remains unknown. In this study, we employed traditional mutant isolation approaches using Mycobacterium smegmatis, a non-pathogenic M. tuberculosis surrogate. We were only able to isolate mutants with decreased susceptibility to selamectin using the ∆nucS mutator M. smegmatis strain. This phenotype was caused by mutations in mps1 and mmpL11. Two of these mutants were used for a second experiment in which high-level selamectin-resistant mutants were isolated; however, specific mutations driving the phenotypic change to high-level resistance could not be identified. The susceptibility to selamectin in these mutants was restored to the basal level by subinhibitory concentrations of ethambutol. The selection of ethambutol resistance in a high-level selamectin-resistant mutant also resulted in multiple colonies becoming susceptible to selamectin again. These colonies carried mutations in embB, suggesting that the integrity of the cell envelope is a prerequisite for selamectin resistance. The absence of increased susceptibility to selamectin in an embB deletion strain demonstrated that the target of selamectin is not cytosolic. Our data show that the concurrence of specific multiple mutations and complete integrity of the mycobacterial envelope are necessary for selamectin resistance. Our studies provide first-time insights into the antimycobacterial mode of action of the antiparasitic avermectins.IMPORTANCETuberculosis is the deadliest infectious disease of the 21st century. New antibiotics are needed to improve treatment. However, developing new drugs is costly and lengthy. Drug repurposing is an alternative to the traditional drug discovery process. The avermectins are a family of drugs used to treat parasitic infections that are active against Mycobacterium tuberculosis, the bacterium that causes tuberculosis. However, their mode of action in mycobacteria remains unknown. Understanding how avermectins kill mycobacteria can facilitate its development as an anti-mycobacterial drug, including against M. tuberculosis.In this study, we used Mycobacterium smegmatis, a non-pathogenic M. tuberculosis surrogate model to understand the molecular mechanisms of how selamectin (a drug of the avermectin family selected for this study as a model) acts against mycobacteria. Our data show that the generation of resistance to selamectin is unlikely and that complete integrity of the mycobacterial envelope is necessary for selamectin resistance, providing first-time insights into the antimycobacterial mode of action of the avermectins.

PMID:40197087 | DOI:10.1128/spectrum.02332-24