Discov Oncol. 2025 Jan 14;16(1):44. doi: 10.1007/s12672-025-01779-x.

ABSTRACT

BACKGROUND: Thyroid carcinoma (THCA) is the most common cancer of the endocrine system. Natural killer (NK) cell play an important role in tumor immune surveillance. The aim of this study was to explore the possible molecular mechanisms involved in NK cell in THCA to help the management and treatment of the disease.

METHODS: All data were downloaded from public databases. Candidate hub genes associated with NK cell in THCA were identified by limma, WGCNA and singleR packages. Functional enrichment analysis was performed on the candidate hub genes. Hub genes associated with NK cell were identified by Pearson correlation analysis. The mRNA-miRNA-lncRNA and transcription factors (TF) networks were constructed and the drug was predicted.

RESULTS: The infiltration level of NK cell in THCA tissues was higher than that in paracancerous tissues. KEGG functional enrichment analysis only obtained two signaling pathways, thyroid hormone synthesis and mineral absorption. CTSC, FN1, SLC34A2 and TMSB4X identified by Pearson correlation analysis were considered as the hub genes. Receiver operating characteristic analysis suggested that hub genes may be potential diagnostic biomarkers. In mRNA-miRNA-lncRNA network, FN1 had the highest correlation with IQCH-AS1, and IQCH-AS1 was also correlated with hsa-miR-543. In addition, FN1 and RUNX1 were also found to have the highest correlation in TF network. Finally, NK cell-related drugs belinostat and vorinostat were identified based on ASGARD.

CONCLUSION: The identification of important signaling pathways, molecules and drugs provides potential research directions for further research in THCA and contributes to the development of diagnostic and therapeutic approaches for this disease.

PMID:39808350 | DOI:10.1007/s12672-025-01779-x

Sci Rep. 2025 Jan 13;15(1):1836. doi: 10.1038/s41598-024-83767-9.

ABSTRACT

Tyrosine-protein kinase Src plays a key role in cell proliferation and growth under favorable conditions, but its overexpression and genetic mutations can lead to the progression of various inflammatory diseases. Due to the specificity and selectivity problems of previously discovered inhibitors like dasatinib and bosutinib, we employed an integrated machine learning and structure-based drug repurposing strategy to find novel, targeted, and non-toxic Src kinase inhibitors. Different machine learning models including random forest (RF), k-nearest neighbors (K-NN), decision tree, and support vector machine (SVM), were trained using already available bioactivity data of Src kinase targeting compounds. The performance evaluation of these models demonstrated SVM as the best model, which was further utilized to shortlist 51 highly potent compounds by screening an FDA-approved library of 1040 drugs. Molecular docking and molecular dynamic simulation were subsequently employed to evaluate the binding affinity and stability of the proposed compounds. Orlistat, acarbose and afatinib were identified as the potent leads, demonstrating stable conformations and stronger interactions, validated by root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (RoG), and hydrogen bond analyses. Molecular Mechanics/Generalized Born Surface Area (MMGBSA) analysis validated their binding affinities by providing comparably lower binding free energies for orlistat (- 33.4743 ± 3.8908), acarbose (- 19.5455 ± 5.4702), and afatinib (- 36.4944 ± 5.4929) than the control, dasatinib (- 13.7785 ± 5.8058). Finally, toxicity analysis revealed orlistat and acarbose as the possible safer therapeutics by eliminating afatinib as it showed significant toxicity concerns. Our investigation supports the advance computational methods utilization in the field of drug discovery and suggest further experimental validation of proposed inhibitors of Src kinase for their safer use against inflammatory diseases. The ultimate aim of this study is to advance the development of effective treatments for inflammatory diseases, linked with Src overexpression.

PMID:39805859 | DOI:10.1038/s41598-024-83767-9

Pigment Cell Melanoma Res. 2025 Jan;38(1):e13225. doi: 10.1111/pcmr.13225.

ABSTRACT

Beta-blockers have generated an exciting discourse for their potential as a cheap, safe, and effective adjunctive therapy for cutaneous melanoma patients, but the field remains murky. This systematic review investigates the association between beta-blocker use and survival outcomes in cutaneous melanoma patients. We reviewed 12 studies with 21,582 patients in a network meta-analysis and found a benefit between beta-blocker use and disease-free survival but no other significant association for melanoma-specific or overall survival. However, some evidence suggests that pan-selective beta-blockers, rather than cardio-selective ones, may have a protective effect. We conclude that the current evidence is insufficient to recommend beta-blockers for melanoma treatment but suggest further research focusing on pan-selective beta-blockers to clarify their potential benefits.

PMID:39804765 | DOI:10.1111/pcmr.13225

RSC Adv. 2025 Jan 9;15(2):748-753. doi: 10.1039/d4ra07449a. eCollection 2025 Jan 9.

ABSTRACT

Due to their considerable chemical diversity, metal compounds are attracting increasing and renewed attention from the scientific and medical communities as potential antimicrobial agents to combat the growing problem of antibiotic resistance. The development of metal compounds as antimicrobial agents typically follows classical drug discovery procedures and suffers from the same problems; indeed, these procedures can be very expensive and time-consuming, and carry an intrinsically high risk of failure. Here, we show how some established drug discovery approaches can be conveniently and successfully applied to antimicrobial metal compounds to provide some shortcuts for faster clinical translation of new treatments. Specifically, we refer to (i) drug repurposing, (ii) drug combination and (iii) drug targeting by bioconjugation; some relevant examples will be illustrated.

PMID:39802470 | PMC:PMC11712697 | DOI:10.1039/d4ra07449a

Mol Ther Oncol. 2024 Nov 23;32(4):200911. doi: 10.1016/j.omton.2024.200911. eCollection 2024 Dec 19.

ABSTRACT

Drug repurposing has potential to improve outcomes for high-grade serous ovarian cancer (HGSOC). Repurposing drugs with PARP family binding activity may produce cytotoxic effects through the multiple mechanisms of PARP including DNA repair, cell-cycle regulation, and apoptosis. The aim of this study was to determine existing drugs that have PARP family binding activity and can be repurposed for treatment of HGSOC. In silico ligand-based virtual screening (BLAZE) was used to identify drugs with potential PARP-binding activity. The list was refined by dosing, known cytotoxicity, lipophilicity, teratogenicity, and side effects. The highest ranked drug, efavirenz, progressed to in vitro testing. Molecularly characterized HGSOC cell lines, 3D hydrogel-encapsulated models, and patient-derived organoid models were used to determine the IC50 for efavirenz, cell death, apoptosis, PARP1 enzyme expression, and activity in intact cancer cells following efavirenz treatment. The IC50 for efavirenz was 26.43-45.85 μM for cells in two dimensions; 27.81 μM-54.98 μM in three dimensions, and 14.52 μM-42.27 μM in HGSOC patient-derived organoids. Efavirenz decreased cell viability via inhibition of PARP; increased CHK2 and phosphor-RB; increased cell-cycle arrest via decreased CDK2; increased γH2AX, DNA damage, and apoptosis. The results of this study suggest that efavirenz may be a viable treatment for HGSOC.

PMID:39802157 | PMC:PMC11719850 | DOI:10.1016/j.omton.2024.200911

Fundam Clin Pharmacol. 2025 Feb;39(1):e13052. doi: 10.1111/fcp.13052.

ABSTRACT

Drug repurposing of well-established drugs to be targeted against lung cancer has been a promising strategy. Bosentan is an endothelin 1 (ET-1) blocker widely used in pulmonary hypertension. The current experiment intends to inspect the anticancer and antiangiogenic mechanism of bosentan targeting epidermal growth factor receptor (EGFR) /extra-cellular Signal Regulated Kinase (ERK) /c-Jun/vascular endothelial growth factor (VEGF) carcinogenic pathway. BALB/c mice were randomized into four groups, the first received the vehicle, the second received 100 mg/kg oral bosentan alone, the third has non-small cell lung cancer (NSCLC) induced by two doses of 1.5 g/kg urethane i.p. and finally the fourth has NSCLC received bosentan. To determine the anti-proliferative impact of bosentan, cytokeratin 19 fragments (CYFRA 21-1) level was assessed, and Ki-67 positive cells were counted by immunohistochemical (IHC). Molecular expression of EGFR via IHC, relative expression of p-ERK1/2 and p-c-Jun via western blotting and caspase 3, Bcl-2 Associated X-protein (BAX)/B-cell lymphoma 2 (Bcl-2) ratio and VEGF via ELISA were quantified. Bosentan showed pronounced improvement in lung index and histopathological examinations. Bosentan exerted a noticeable arrest of lung cancer growth indicated by the attenuation of CYFRA 21-1 and Ki-67 positive cell counts besides the boost of BAX/Bcl-2 ratio and caspase 3. Bosentan induced a remarkable decline of EGFR, T-ERK1/2/p-ERK1/2, T-c-Jun/p-c-Jun, and VEGF. Bosentan induced cytotoxic and anti-angiogenic impact through regulation of EGFR/ERK/c-Jun/VEGF axis suggesting its potential therapeutic impact against lung cancer.

PMID:39801131 | DOI:10.1111/fcp.13052

Turk J Pharm Sci. 2025 Jan 10;21(6):566-576. doi: 10.4274/tjps.galenos.2024.49768.

ABSTRACT

INTRODUCTION: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), from the family Coronaviridae, is the seventh known coronavirus to infect humans and cause acute respiratory syndrome. Although vaccination efforts have been conducted against this virus, which emerged in Wuhan, China, in December 2019 and has spread rapidly around the world, the lack of an Food and Drug Administration-approved antiviral agent has made drug repurposing an important approach for emergency response during the COVID-19 pandemic. The aim of this study was to investigate the potential of H1-antihistamines as antiviral agents against SARS-CoV-2 RNA-dependent RNA polymerase enzyme.

MATERIALS AND METHODS: Using molecular docking techniques, we explored the interactions between H1-antihistamines and RNA-dependent RNA polymerase (RdRp), a key enzyme involved in viral replication. The three-dimensional structure of 37 H1-antihistamine molecules was drawn and their energies were minimized using Spartan 0.4. Subsequently, we conducted a docking study with Autodock Vina to assess the binding affinity of these molecules to the target site. The docking scores and conformations were then visualized using Discovery Studio.

RESULTS: The results examined showed that the docking scores of the H1-antihistamines were between 5.0 and 8.3 kcal/mol. These findings suggested that among all the analyzed drugs, bilastine, fexofenadine, montelukast, zafirlukast, mizolastine, and rupatadine might bind with the best binding energy (< -7.0 kcal/mol) and inhibit RdRp, potentially halting the replication of the virus.

CONCLUSION: This study highlights the potential of H1-antihistamines in combating COVID-19 and underscores the value of computational approaches in rapid drug discovery and repurposing efforts. Finally, experimental studies are required to measure the potency of H1-antihistamines before their clinical use against COVID-19 as RdRp inhibitors.

PMID:39801109 | DOI:10.4274/tjps.galenos.2024.49768

EBioMedicine. 2025 Jan 11;112:105553. doi: 10.1016/j.ebiom.2024.105553. Online ahead of print.

ABSTRACT

BACKGROUND: Lupus nephritis (LN) is one of the most common and severe complications of systemic lupus erythematosus (SLE). Multitarget therapy (MT) achieves a 20% higher complete remission (CR) rate compared to conventional therapy in LN management. Intrigued by its excellent clinical efficacy, we aimed to develop a single-agent therapy with comparable efficacy to MT, offering a simplified treatment regimen.

METHODS: AZD1152, an Aurora kinase B (Aurkb) inhibitor, was identified through transcriptomic analyses and the L1000 CMap drug repurposing database. The therapeutic efficacy of AZD1152 was evaluated in MRL/lpr mice. Transcriptome sequencing and functional assays were performed to elucidate its mechanisms of action. Aurkb expression and its clinical relevance were assessed in lupus-prone mice and patients with LN.

FINDINGS: AZD1152 significantly attenuated systemic immune activation and renal injury in MRL/lpr mice, demonstrating efficacy comparable to MT regimens in animal studies. AZD1152 treatment modulated immune-inflammatory pathways in the kidney. Aurkb expression was upregulated in T cells infiltrating the renal interstitium in LN. Additionally, Aurkb expression levels positively correlated with the activity index (AI) and serum creatinine (Scr) in patients with LN. Mechanistic studies revealed that AZD1152 exerts therapeutic effects primarily by inhibiting T-cell proliferation.

INTERPRETATION: This study presents a drug development strategy that integrates clinically validated LN therapies with drug repurposing approaches. This strategy could accelerate drug development and clinical translation processes for LN.

FUNDING: A full list of funding sources can be found in the acknowledgements section.

PMID:39799765 | DOI:10.1016/j.ebiom.2024.105553

Sci Rep. 2025 Jan 11;15(1):1690. doi: 10.1038/s41598-025-85900-8.

ABSTRACT

Primary aldosteronism (PA), characterized by autonomous aldosterone overproduction, is a major cause of secondary hypertension with significant cardiovascular complications. Current treatments mainly focus on symptom management rather than addressing underlying mechanisms. This study aims to discover novel therapeutic targets for PA using integrated bioinformatics and experimental validation approaches. We employed a systematic approach combining: gene identification through transcriptome-wide association studies (TWAS); causal inference using summary data-based Mendelian randomization (SMR) and two-sample Mendelian randomization (MR) analyses; additional analyses included phenome-wide association analysis, enrichment analysis, protein-protein interaction (PPI) networks, drug repurposing, molecular docking and clinical validation through aldosterone-producing adenomas (APAs) tissue. Through systematic screening and prioritization, we identified 163 PA-associated genes, of which seven emerged as potential drug targets: CEP104, HIP1, TONSL, ZNF100, SHMT1, and two long non-coding RNAs (AC006369.2 and MRPL23-AS1). SHMT1 was identified as the most promising target, showing significantly elevated expression in APAs compared to adjacent non-tumorous tissues. Drug repurposing analysis identified four potential SHMT1-targeting compounds (Mimosine, Pemetrexed, Leucovorin, and Irinotecan), supported by molecular docking studies. The integration of multiple bioinformatics methods and experimental validation successfully identified novel drug targets for hyperaldosteronism. SHMT1, in particular, represents a promising candidate for future therapeutic development. These findings provide new opportunities for developing causative treatments for PA, though further clinical validation is warranted.

PMID:39799159 | DOI:10.1038/s41598-025-85900-8

J Comput Chem. 2025 Jan 15;46(2):e70029. doi: 10.1002/jcc.70029.

ABSTRACT

Phosphodiesterase 5 (PDE5) inhibitors have shown great potential in treating Alzheimer's disease by improving memory and cognitive function. In this study, we evaluated fluspirilene, a drug commonly used to treat schizophrenia, as a potential PDE5 inhibitor using computational methods. Molecular docking revealed that fluspirilene binds strongly to PDE5, supported by hydrophobic and aromatic interactions. Molecular dynamics simulations confirmed that the fluspirilene-PDE5 complex is stable and maintains its structural integrity over time. Binding energy calculations further highlighted favorable interactions, indicating that the drug forms a strong and stable bond with PDE5. Additional analyses, including studies of protein dynamics and energy landscape mapping, revealed how the drug interacts dynamically with PDE5, adapting to different conformations and maintaining stability. These findings suggest that fluspirilene may modulate PDE5 activity, potentially offering therapeutic benefits for Alzheimer's disease. This study provides strong evidence for repurposing fluspirilene as a treatment for Alzheimer's and lays the foundation for further experimental and clinical investigations.

PMID:39797567 | DOI:10.1002/jcc.70029

Cancers (Basel). 2025 Jan 3;17(1):132. doi: 10.3390/cancers17010132.

ABSTRACT

BACKGROUND/OBJECTIVES: Intrahepatic cholangiocarcinoma (iCCA) is a malignant liver tumor with a rising global incidence and poor prognosis, largely due to late-stage diagnosis and limited effective treatment options. Standard chemotherapy regimens, including cisplatin and gemcitabine, often fail because of the development of multidrug resistance (MDR), leaving patients with few alternative therapies. Doxycycline, a tetracycline antibiotic, has demonstrated antitumor effects across various cancers, influencing cancer cell viability, apoptosis, and stemness. Based on these properties, we investigated the potential of doxycycline to overcome gemcitabine resistance in iCCA.

METHODS: We evaluated the efficacy of doxycycline in two MDR iCCA cell lines, MT-CHC01R1.5 and 82.3, assessing cell cycle perturbation, apoptosis induction, and stem cell compartment impairment. We assessed the in vivo efficacy of combining doxycycline and gemcitabine in mouse xenograft models.

RESULTS: Treatment with doxycycline in both cell lines resulted in a significant reduction in cell viability (IC50 ~15 µg/mL) and induction of apoptosis. Doxycycline also diminished the cancer stem cell population, as indicated by reduced cholangiosphere formation. In vivo studies showed that while neither doxycycline nor gemcitabine alone significantly reduced tumor growth, their combination led to marked decreases in tumor volume and weight at the study endpoint. Additionally, metabolic analysis revealed that doxycycline reduced glucose uptake in tumors, both as a monotherapy and more effectively in combination with gemcitabine.

CONCLUSIONS: These findings suggest that doxycycline, especially in combination with gemcitabine, can restore chemotherapy sensitivity in MDR iCCA, providing a promising new strategy for improving outcomes in this challenging disease.

PMID:39796759 | DOI:10.3390/cancers17010132

Foods. 2025 Jan 2;14(1):102. doi: 10.3390/foods14010102.

ABSTRACT

Oncostatin M (OSM) plays a crucial role in diverse inflammatory reactions. Although the food bioactive compound naringenin (NAR) exerts various useful effects, including antitussive, anti-inflammatory, hepatoprotective, renoprotective, antiarthritic, antitumor, antioxidant, neuroprotective, antidepressant, antinociceptive, antiatherosclerotic, and antidiabetic effects, the modulatory mechanism of NAR on OSM expression in neutrophils has not been specifically reported. In the current work, we studied whether NAR modulates OSM release in neutrophil-like differentiated (d)HL-60 cells. To assess the modulatory effect of NAR, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunofluorescence assay were employed. While exposure to granulocyte-macrophage colony-stimulating factor (GM-CSF) induced elevated OSM release and mRNA expression, the elevated OSM release and mRNA expression were diminished by the addition of NAR in dHL-60 cells. While the phosphorylation of phosphatidylinositol 3-kinase, protein kinase B (Akt), and nuclear factor (NF)-κB was upregulated by exposure to GM-CSF, the upregulated phosphorylation was inhibited by the addition of NAR in dHL-60 cells. Consequently, the results indicate that the food bioactive compound NAR may have a positive effect on health (in health promotion and improvement) or may play a role in the prevention of inflammatory diseases.

PMID:39796391 | DOI:10.3390/foods14010102

Int J Mol Sci. 2025 Jan 3;26(1):364. doi: 10.3390/ijms26010364.

ABSTRACT

This review describes our current understanding of the role of the mitochondria in the repurposing of the anti-diabetes drugs metformin, gliclazide, GLP-1 receptor agonists, and SGLT2 inhibitors for additional clinical benefits regarding unhealthy aging, long COVID, mental neurogenerative disorders, and obesity. Metformin, the most prominent of these diabetes drugs, has been called the "Drug of Miracles and Wonders," as clinical trials have found it to be beneficial for human patients suffering from these maladies. To promote viral replication in all infected human cells, SARS-CoV-2 stimulates the infected liver cells to produce glucose and to export it into the blood stream, which can cause diabetes in long COVID patients, and metformin, which reduces the levels of glucose in the blood, was shown to cut the incidence rate of long COVID in half for all patients recovering from SARS-CoV-2. Metformin leads to the phosphorylation of the AMP-activated protein kinase AMPK, which accelerates the import of glucose into cells via the glucose transporter GLUT4 and switches the cells to the starvation mode, counteracting the virus. Diabetes drugs also stimulate the unfolded protein response and thus mitophagy, which is beneficial for healthy aging and mental health. Diabetes drugs were also found to mimic exercise and help to reduce body weight.

PMID:39796218 | DOI:10.3390/ijms26010364

Int J Mol Sci. 2025 Jan 1;26(1):315. doi: 10.3390/ijms26010315.

ABSTRACT

Eumycetoma, a chronic fungal infection caused by Madurella mycetomatis, is a neglected tropical disease characterized by tumor-like growths that can lead to permanent disability and deformities if untreated. Predominantly affecting regions in Africa, South America, and Asia, it imposes significant physical, social, and economic burdens. Current treatments, including antifungal drugs like itraconazole, often show variable efficacy, with severe cases necessitating surgical intervention or amputation. Drug discovery for eumycetoma faces challenges due to limited understanding of the disease's molecular mechanisms and the lack of 3D structures for key targets such as Madurella mycetomatis CYP51, a well-known target for azoles' antifungal agents. To address these challenges, this study employed computational approaches, including homology modeling, virtual screening, free energy calculations, and molecular dynamics simulations, to repurpose FDA-approved drugs as potential treatments for eumycetoma targeting Madurella mycetomatis CYP51. To this end, a library of 2619 FDA-approved drugs was screened, identifying three promising candidates: montelukast, vilanterol, and lidoflazine. These compounds demonstrated favorable binding affinities, strong interactions with critical residues of the homology model of Madurella mycetomatis CYP51, and stability in molecular dynamics simulations, offering potential for further investigation as effective therapeutic options for eumycetoma.

PMID:39796172 | DOI:10.3390/ijms26010315

Neurotherapeutics. 2025 Jan 9:e00522. doi: 10.1016/j.neurot.2024.e00522. Online ahead of print.

ABSTRACT

Paclitaxel (PCX) based treatments, commonly used to treat breast, ovarian and lung cancers, have the highest incidence of chemotherapy-induced neuropathic pain, affecting from 38 to 94 ​% of patients. Unfortunately, analgesic treatments are not always effective for PCX-induced neuropathic pain (PINP). This study aimed to evaluate the antinociceptive effect of clavulanic acid (CLAV), a clinically used β-lactam molecule, in both therapeutic and preventive contexts in mice with PINP. A single dose of CLAV administered after the onset of PINP significantly reduced mechanical hyperalgesia. Interestingly, preventive administration of CLAV prevented PINP development. The effect of preventive CLAV on PINP was associated with increased levels of IL-10 and IFN-β in serum, and decreased levels of IL-1β and TNF-α in both the serum and CNS. Immunostaining experiments revelated that CLAV increased the levels of glutamate transporter type 1 (GLT-1) and toll-like receptor type 4 (TLR4) in the spinal cord, while reducing levels of the astrocytic marker the glial fibrillary acidic protein (GFAP). Notably, co-incubation with CLAV and PCX in triple-negative breast cancer cells did not interfere with PCX-induced cytotoxic effects. Hence, these findings suggest that CLAV could be employed as a clinical treatment aimed at preventing PINP without compromission the cytotoxic efficacy of PCX.

PMID:39794241 | DOI:10.1016/j.neurot.2024.e00522

Mol Cell Proteomics. 2025 Jan 8:100905. doi: 10.1016/j.mcpro.2025.100905. Online ahead of print.

ABSTRACT

Protein phosphorylation plays a crucial role in regulating diverse biological processes. Perturbations in protein phosphorylation are closely associated with downstream pathway dysfunctions, while alterations in protein expression could serve as sensitive indicators of pathological status. However, there are currently few methods that can accurately identify the regulatory links between protein phosphorylation and expression, given issues like reverse causation and confounders. Here, we present Phoslink, a causal inference model to infer causal effects between protein phosphorylation and expression, integrating prior evidence and multi-omics data. We demonstrated the feasibility and advantages of our method under various simulation scenarios. Phoslink exhibited more robust estimates and lower FDR than commonly used Pearson and Spearman correlations, with better performance than canonical IV selection methods for Mendelian randomization. Applying this approach, we identified 345 causal links involving 109 phosphosites and 310 proteins in 79 lung adenocarcinoma (LUAD) samples. Based on these links, we constructed a causal regulatory network and identified 26 key regulatory phosphosites as regulators strongly associated with LUAD. Notably, 16 of these regulators were exclusively identified through phosphosite-protein causal regulatory relationships, highlighting the significance of causal inference. We explored potentially druggable phosphoproteins and provided critical clues for drug repurposing in LUAD. We also identified significant mediation between protein phosphorylation and LUAD through protein expression. In summary, our study introduces a new approach for causal inference in phosphoproteomics studies. Phoslink demonstrates its utility in potential drug target identification thereby accelerating the clinical translation of cancer proteomics and phosphoproteomic data.

PMID:39793886 | DOI:10.1016/j.mcpro.2025.100905

Eur J Med Chem. 2025 Jan 4;285:117245. doi: 10.1016/j.ejmech.2025.117245. Online ahead of print.

ABSTRACT

Breast cancer, a leading cause of cancer-related mortality in women, is characterized by genomic instability and aberrant gene expression, often influenced by noncanonical nucleic acid structures such as G-quadruplexes (G4s). These structures, commonly found in the promoter regions and 5'-untranslated RNA sequences of several oncogenes, play crucial roles in regulating transcription and translation. Stabilizing these G4 structures offers a promising therapeutic strategy for targeting key oncogenic pathways. In this study, we employed a drug repurposing approach to identify FDA-approved drugs capable of binding and stabilizing G4s in breast cancer-related genes. Using ligand-based virtual screening and biophysical methods, we identified several promising compounds, such as azelastine, belotecan, and irinotecan, as effective G4 binders, with significant antiproliferative effects in breast cancer cell lines. Notably, belotecan and irinotecan exhibited a synergistic mechanism, combining G4 stabilization with their established topoisomerase I inhibition activity to enhance cytotoxicity in cancer cells. Our findings support the therapeutic potential of G4 stabilization in breast cancer, validate drug repurposing as an efficient strategy to identify G4-targeting drugs, and highlight how combining G4 stabilization with other established drug activities may improve anticancer efficacy.

PMID:39793440 | DOI:10.1016/j.ejmech.2025.117245

Int J Environ Health Res. 2025 Jan 10:1-11. doi: 10.1080/09603123.2025.2451623. Online ahead of print.

ABSTRACT

This study utilized a validated questionnaire that aimed to assess pharmacists' awareness and attitude towards drug repurposing for antimicrobial use. Despite the reasonable awareness, pharmacists reported unfavourable attitudes. Pharmacists with a B.Pharm. or Pharm.D. degree reported less awareness than pharmacists with a master's or PhD degree. In contrast, pharmacists who dispensed fewer than 10 prescriptions or 10-29 prescriptions had significantly higher awareness than those who dispensed 30 prescriptions daily or more. Pharmacists who had 1-5 years of experience and those who dispensed less than 10 prescriptions daily had significantly lower attitude scores than their counterpats. The most reported facilitator was the reduced risk of antimicrobial resistance, while the most reported barrier was patient safety. Pharmacists' perception of drug repurposing for antimicrobial needs to improve via implementing educational sessions that highlight the impact of drug repurposing on supporting the fight against antimicrobial resistance and promoting a more sustainable and resilient healthcare system.

PMID:39792370 | DOI:10.1080/09603123.2025.2451623

J Appl Microbiol. 2025 Jan 9:lxaf012. doi: 10.1093/jambio/lxaf012. Online ahead of print.

ABSTRACT

AIMS: To investigate the effects of simvastatin as an antimicrobial, considering its influence on the mevalonate pathway and on the bacterial cell wall of Staphylococcus aureus.

METHODS AND RESULTS: S. aureus ATCC 29213 and 33591 were exposed to simvastatin in the presence of exogenous mevalonate to determine whether mevalonate could reverse the inhibition. S. aureus was also treated with simvastatin and gene expression analysis assays were performed to evaluate genes associated with the mevalonate pathway (mvaA, mvaS, mvaK1, and mvaK2), peptidoglycan synthesis (uppS, uppP, and murG), and cell wall stress (vraX, sgtB, and tcaA). Transmission electron microscopy was used to identify the presence of morphological changes. The data were compared using two-way ANOVA and Bonferroni post-test, or the Mann-Whitney test. Addition of exogenous mevalonate was able to partially or completely reverse the inhibition caused by simvastatin. A significant increase of the vraX gene and a reduction of the mvaA gene were observed, together with changes in bacterial morphology.

CONCLUSION: Simvastatin can exert its antimicrobial effect by means of changes in the cell wall associated with the mevalonate pathway.

PMID:39788721 | DOI:10.1093/jambio/lxaf012

Int J Biol Macromol. 2025 Jan 7:139590. doi: 10.1016/j.ijbiomac.2025.139590. Online ahead of print.

ABSTRACT

SARS-CoV-2 encodes a 3C-like protease (3CLpro) that is essential for viral replication. This cysteine protease cleaves viral polyproteins to release functional nonstructural proteins, making it a prime target for antiviral drug development. We investigated the inhibitory effects of halicin, a known c-Jun N-terminal kinase inhibitor, on 3CLpro. Mass spectrometry and crystallographic analysis revealed that halicin covalently binds to several cysteine residues in 3CLpro. As expected, Cys145, the catalytic residue, was found to be the most targeted residue by halicin. Secondly, Cys44 was found to be modified, suggesting a potential inhibitory role of this residue. A mutant protease (Cys44Ala) was generated to further understand the function of Cys44. In silico and enzymatic assays showed that the mutation significantly reduced the stability and activity of 3CLpro, indicating the importance of Cys44 in maintaining the active conformation of the protease. Differential scanning fluorimetry assays confirmed this evidence, showing a reduced thermal stability of the mutant compared to the wild-type protease. Our results highlight the potential of halicin as a multi-target inhibitor of 3CLpro and underline the importance of Cys44 in the function of the protease. These findings contribute to the development of effective antiviral therapies against COVID-19 by targeting critical residues in 3CLpro.

PMID:39788258 | DOI:10.1016/j.ijbiomac.2025.139590