ACS Chem Neurosci. 2025 May 31. doi: 10.1021/acschemneuro.5c00082. Online ahead of print.

ABSTRACT

Caspase-3-dependent apoptosis is believed to contribute to the brain injury of ischemic stroke, and a caspase-3 inhibitor has been repeatedly reported to reduce the brain injury of ischemic stroke. However, currently recognized caspase-3 inhibitors are still only used as a research tool, and none of them is available in the clinic to treat brain injury of ischemic stroke. Based on the concept of drug repositioning and bioinformatics techniques, we have identified Cerdulatinib, a multitargeted tyrosine kinase inhibitor to treat tumors and immune-related diseases in the clinic, as a potential caspase-3 inhibitor. This study aims to explore the effect of Cerdulatinib on brain injury from ischemic stroke and the underlying mechanisms. In mice with ischemic stroke, Cerdulatinib significantly decreased infarct volume and improved sensorimotor function, memory ability, and cognitive function. In nerve cells exposed to hypoxia, Cerdulatinib increased cell viability and decreased LDH release. Mechanistically, Cerdulatinib inhibited the protein level of cleaved caspase-3 and the activity of caspase-3, resulting in a decrease in brain cell apoptosis. Based on these results, we conclude that Cerdulatinib can protect the brain against ischemic injury by reducing apoptosis, which is related to the suppression of caspase-3 cleavage and caspase-3 activity. This study may extend the clinical indications of Cerdulatinib in the treatment of patients with an ischemic stroke.

PMID:40448621 | DOI:10.1021/acschemneuro.5c00082

Spectrochim Acta A Mol Biomol Spectrosc. 2025 May 27;342:126487. doi: 10.1016/j.saa.2025.126487. Online ahead of print.

ABSTRACT

Drug repositioning and reuse is a cost-effective strategy for the development of new drugs, and drug co-crystal is a fast and effective technical means. Acetylsalicylic acid is a BCS II drug, which has the limitations of high permeability and low solubility, and the safety and efficacy of the drug have been greatly affected. Co-crystallization with other forming agents is considered to be a promising technical means, which can not only increase the solubility, but also improve the dissolution rate and stability. In this paper, the cocrystal of acetylsalicylic acid and arginine was prepared by grinding method. The physical and chemical characterization of the raw material, the mixture and the obtained cocrystal was carried out by XRD, terahertz spectroscopy (THz-TDS) and Raman spectroscopy (Raman). The obvious difference was observed on the characteristic peaks of the cocrystal, which proved the formation of the cocrystal. Understanding the basic properties of lattice vibration during the eutectic process is challenging, yet it can be accomplished through theoretical calculations. By employing density-functional theory (DFT) calculations, the molecular configurations and vibration spectra of the two drug cocrystals can be obtained, enabling a deeper understanding of the vibration modes of drug molecules in the low-frequency range. Moreover, this study demonstrates the sensitivity of terahertz time-domain spectroscopy (TDS) technology in detecting intermolecular hydrogen-bond interactions in drug cocrystals. When comparing cocrystal molecules with active pharmaceutical ingredient (API) molecules, it is found that cocrystals possess better binding energy, driven by intermolecular hydrogen bonds and dispersion forces.

PMID:40446719 | DOI:10.1016/j.saa.2025.126487

PLoS One. 2025 May 30;20(5):e0324146. doi: 10.1371/journal.pone.0324146. eCollection 2025.

ABSTRACT

Drug-target interactions (DTIs) play a critical role in drug discovery and repurposing. Deep learning-based methods for predicting drug-target interactions are more efficient than wet-lab experiments. The extraction of original and substructural features from drugs and proteins plays a key role in enhancing the accuracy of DTI predictions, while the integration of multi-feature information and effective representation of interaction data also impact the precision of DTI forecasts. Consequently, we propose a drug-target interaction prediction model, SSCPA-DTI, based on substructural subsequences and a cross co-attention mechanism. We use drug SMILES sequences and protein sequences as inputs for the model, employing a Multi-feature information mining module (MIMM) to extract original and substructural features of DTIs. Substructural information provides detailed insights into molecular local structures, while original features enhance the model's understanding of the overall molecular architecture. Subsequently, a Cross-public attention module (CPA) is utilized to first integrate the extracted original and substructural features, then to extract interaction information between the protein and drug, addressing issues such as insufficient accuracy and weak interpretability arising from mere concatenation without interactive integration of feature information. We conducted experiments on three public datasets and demonstrated superior performance compared to baseline models.

PMID:40445972 | DOI:10.1371/journal.pone.0324146

Front Pharmacol. 2025 May 13;16:1599297. doi: 10.3389/fphar.2025.1599297. eCollection 2025.

ABSTRACT

Major depressive disorder (MDD) is a serious neuropsychiatric condition that affects millions of people worldwide, causing significant psychological distress and lifestyle deterioration. The serotonin transporter, which plays a critical role in regulating the uptake of serotonin (5-HT) back into presynaptic cells, is a primary target for antidepressants. Though selective serotonin reuptake inhibitors (SSRIs) are still the pharmacologic treatment of choice, alternative methods remain in demand to enhance the efficacy of treatment and offer more therapeutic options. Drug repurposing provides an efficient solution to speed up antidepressant research because it identifies existing FDA-approved medications that might inhibit the serotonin transporter. A virtual screening method was integrated into the study that examined 3620 FDA-approved drugs to discover new repurposed serotonin transporter-inhibiting molecules. The binding affinity, structural stability, and inhibitory potential were assessed using molecular docking and molecular dynamics (MD) simulations. Among the screened compounds, Flunarizine, a well-known calcium channel blocker, emerged as a promising serotonin transporter inhibitor due to its strong and stable binding configuration within the transporter's active site. Detailed molecular docking studies revealed that Flunarizine formed key interactions with critical residues of the serotonin transporter, suggesting its potential as an effective modulator. Subsequent 500-nanosecond MD simulations further confirmed the stability of the serotonin transporter-Flunarizine complex, demonstrating minimal structural deviations and maintaining crucial dynamic properties throughout the simulation trajectory. These findings highlight Flunarizine's potential for repurposing as a novel therapeutic agent targeting serotonin transport modulation. The study provides a solid foundation for further preclinical and clinical investigations into the antidepressant repurposing of Flunarizine.

PMID:40444039 | PMC:PMC12120357 | DOI:10.3389/fphar.2025.1599297

BMC Med. 2025 May 30;23(1):321. doi: 10.1186/s12916-025-04127-6.

ABSTRACT

BACKGROUND: Insulin is known to be associated with a higher risk of coronary artery disease (CAD), but molecular mechanisms remain unclear. This study aimed to explore protein-mediated pathways linking fasting insulin to CAD using Mendelian randomization (MR).

METHODS: This MR study examined the association between fasting insulin and CAD using genome-wide association study (GWAS) data from MAGIC and CARDIoGRAMplusC4D. To investigate underlying mechanisms, a two-step proteome-wide MR analysis was conducted. First, associations of fasting insulin with 2940 circulating proteins were assessed using GWAS of proteomics from UKB-PPP. Proteins affected by insulin were then analyzed for their association with CAD risk. Proteins selected in both steps were considered as potential mediators. Sensitivity analyses to test whether associations are robust to pleiotropy and replication using other GWAS data, including GWAS of proteomics from deCODE and GWAS of CAD from FinnGen Biobank, were performed.

RESULTS: Genetically predicted insulin was associated with a higher risk of CAD (odds ratio 1.79, 95% confidence interval 1.34 to 2.40). At a false discovery rate of 0.05, insulin affected 355 proteins, ten of which were both increased by insulin and linked to a higher risk of CAD. After sensitivity and replication analyses, PLA2G7, GZMA, LDLR, AGRP, and HHEX were identified as reliable mediators. Mediation analyses using non-pleiotropic instruments showed that PLA2G7, GZMA, LDLR, and AGRP explained 19.50%, 6.91%, 19.31%, and 29.66% of insulin's total effect on CAD, respectively.

CONCLUSIONS: This study identified five protein mediators linking insulin to CAD. These proteins could be considered as potential targets to mitigate insulin-related cardiovascular risk, providing novel insights for drug repurposing.

PMID:40442727 | DOI:10.1186/s12916-025-04127-6

J Biomed Res. 2025 May 30:1-12. doi: 10.7555/JBR.39.20250166. Online ahead of print.

ABSTRACT

The comorbidity of skin and gastrointestinal tract (GIT) diseases, primarily driven by the gut-skin axis (GSA), is well-known. However, the genetic contribution to the GSA remains unclear. Here, using genome-wide association study (GWAS) summary statistics from European populations, we performed genome-wide pleiotropic analysis to investigate the shared genetic basis and causal associations between skin and GIT diseases. We observed extensive genetic correlations and overlaps between skin and GIT diseases. A total of 298 pleiotropic loci were identified, 75 of which were colocalized, and 61 exhibited pleiotropic effects across multiple trait pairs, including 2p16.1 ( PUS10), 6p21.32 ( HLA-DRB1), 10q21.2 ( ZNF365), and 19q13.11 ( SLC7A10). Additionally, five novel loci were identified based on the pleiotropic analysis, with RORA at 15q22.2 validated by the latest inflammatory bowel disease GWAS. Gene-based analysis found 394 unique pleiotropic genes, which were enriched in GSA-associated tissues and immune system, whereas protein-protein interaction analysis further revealed the GPCR-cAMP, chromatin remodeling, JAK-STAT, and HLA-mediated immunity pathways coregulate GSA comorbidity. Notably, the JAK-STAT pathway showed strong potential in drug repurposing, with Adalimumab targeting TNF and Ustekinumab targeting IL-12B already used to treat both skin and GIT diseases. Finally, Mendelian randomization analysis suggested five significant causal associations, and subsequent mediation analysis introduced three potential microbiota-GIT-skin pathways. Taken together, our study suggested that the shared genetic factors between skin and GIT diseases are widely distributed across the genome. These findings will improve our understanding of the genetic basis of GSA and offer significant implications for simultaneously treating skin and GIT diseases.

PMID:40441863 | DOI:10.7555/JBR.39.20250166

Exp Parasitol. 2025 May 27:108966. doi: 10.1016/j.exppara.2025.108966. Online ahead of print.

ABSTRACT

Leishmaniasis is a parasitic disease caused by protozoa of the genus Leishmania, the conventional treatments are expensives, high adverse reactions and long-term parenteral administration This study aimed to evaluate the therapeutic potential of the antiviral Oseltamivir (Osv) in microemulsion in the topical treatment of cutaneous leishmaniasis in BALB/c mice infected with Leishmania major. After infection, the mice were divided into five groups (Control, Amphotericin B 3%, Osv 0.5%, Osv 1% and Osv 1%+Amphotericin B 1.5%) and treated for 21 days. Clinical parameters, such as body weight and lesion size, in addition to parasite load, hematological, biochemical and histopathological analyses were evaluated. A significant reduction in the parasite load was observed in the groups treated with Oseltamivir and Amphotericin B (70% to 76.5%), when compared to the control group (95%). Clinical evaluation showed fewer lesions in the treatment groups compared to the control group. Although Amphotericin B alone caused liver and kidney toxicity, treatment with Oseltamivir, alone or in combination with Amphotericin B, did not show any toxicity. In histopathological examination, the groups treated with Oseltamivir showed lower degrees of histopathological alterations. Thus, Oseltamivir, as monotherapy or in combination with Amphotericin B, proved to be effective and safe, representing a promising alternative in the treatment of cutaneous leishmaniasis.

PMID:40441373 | DOI:10.1016/j.exppara.2025.108966

Drug Discov Today. 2025 May 27:104390. doi: 10.1016/j.drudis.2025.104390. Online ahead of print.

ABSTRACT

Drug repurposing leverages existing drugs for new therapeutic uses, offering significant opportunities but facing challenges such as financial and regulatory barriers and the need for robust evidence for an efficient clinical development plan. This paper examines the critical steps in drug repurposing and their role in improving study success rates. It also highlights the support infrastructure provided by the University College London (UCL) Repurposing Therapeutic Innovation Network (TIN), as a partnership model to address these challenges through diverse expertise, enterprise insight, and tailored guidance. By fostering collaborations and offering structured support, the Repurposing TIN aims to accelerate repurposing efforts and deliver patient benefits. We invite potential collaborators to join us in advancing drug repurposing through innovative and strategic approaches.

PMID:40441598 | DOI:10.1016/j.drudis.2025.104390

Regul Toxicol Pharmacol. 2025 May 27:105864. doi: 10.1016/j.yrtph.2025.105864. Online ahead of print.

ABSTRACT

Modified new drugs are pivotal in advancing innovative therapies through repurposing existing therapeutic agents. The regulatory framework, including the pertinent regulations and policies, plays a crucial role in shaping the development and evolution of these drugs. This retrospective study systematically compared the regulatory approvals of modified new drugs via the 505(b)(2) new drug application (NDA) pathway in the United States (US) and Class 2 NDA pathway in China from 2017 to 2023, which focused on distinctions in registration classifications, availability, therapeutic indications, dosage forms, modifications, clinical advantages and clinical study designs. The findings indicate that the US has more detailed and comprehensive classification systems, as well as a higher number of approvals (417 vs. 99). Moreover, the modified new drugs approved in China still exhibit significant gaps in indication distribution, dosage forms, and modifications compared to those in the US. Notably, a greater proportion of confirmatory clinical studies were conducted for Class 2 NDAs (81.4%) than 505(b)(2) NDAs (41.0%), with a significant difference in the use of active controls (48.6% in China vs. 26.4% in the US, P=0.002). Additionally, the combination of emerging technologies in modified new drugs presents both technical and regulatory challenges for authorities. It raises worthwhile questions about how regulators will evaluate medical products developed with entirely new technologies. Therefore, it is recommended that Chinese regulators refine registration classifications, reassess the positioning of modified new drugs, and expand the definition of clinical advantage within the policy and regulatory framework. These measures are essential for addressing unmet medical needs and fostering a conducive ecosystem for the advancement of modified new drugs.

PMID:40441284 | DOI:10.1016/j.yrtph.2025.105864

Front Med (Lausanne). 2025 May 14;12:1576029. doi: 10.3389/fmed.2025.1576029. eCollection 2025.

ABSTRACT

BACKGROUND: Metabolic-associated fatty liver disease (MAFLD) is a prevalent chronic liver condition with significant health implications. Fermented Cordyceps Preparation (FCP) has shown promise in managing metabolic disorders, prompting interest in its potential for MAFLD prevention. There is, however, a lack of large-scale clinical evidence regarding its preventive efficacy and long-term safety.

AIM: We aimed to assess the preventive efficacy and safety of FCP, as regards combatting MAFLD.

METHODS: Propensity score matching was used to select 343 FCP users and 1372 non-users with metabolic syndrome, (MS) as recorded in EMR. These two groups were followed for 750 days, to track the incidence of MAFLD. The Kaplan Meier method was used to calculate the cumulative risk of MAFLD events in each subgroup. A Multiple linear regression model was used to compare the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as between the two groups.

RESULTS: Compared with non-users, FCP users were associated with a 26% decreased risk of MAFLD (hazard ratio 0.74, 95% confidence interval 0.56-0.97). During the follow-up, the changes in both ALT and AST, were insignificantly different between the two groups.

CONCLUSION: These findings highlight the potential of FCP in MAFLD prevention and offer insight into its safety profile, suggesting avenues for further clinical validation and drug repurposing efforts.

PMID:40438375 | PMC:PMC12116537 | DOI:10.3389/fmed.2025.1576029

Sci Rep. 2025 May 28;15(1):18722. doi: 10.1038/s41598-025-02773-7.

ABSTRACT

The COVID-19 pandemic has initiated a global health emergency, with an exigent need for an effective cure. Progressively, drug repurposing is emerging as a promising solution for saving time, cost, and labor. However, the number of drug candidates that have been identified for the treatment of COVID-19 is still insufficient, so more effective and thorough drug exploration strategies are required. In this study, we joined the molecular docking with machine learning approaches to find some prospective therapeutic candidates for COVID-19 treatment. We screened the 5903 approved drugs for their inhibition by targeting the replicating enzyme 3CLpro of SARS-CoV-2. Molecular docking is used to calculate the binding affinities of these drugs towards 3CLpro. We employed several machine learning approaches for QSAR modeling to explore some potential drugs with high binding affinities. Our outcomes demonstrated that the Decision Tree Regression (DTR) model, with the best scores of R² and RMSE, is the most suitable model to explore the potential drugs. We shortlisted six favorable drugs with their respective Zinc IDs (3873365, 85432544, 203757351, 85536956, 8214470, and 261494640) within the range of -15 kcal/mol to -13 kcal/mol. We further examined the physiochemical and pharmacokinetic properties of these most potent drugs. Our study provides an efficient framework to explore the potential drugs against COVID-19 and establishes the impending combination of molecular docking with machine learning approaches to accelerate the identification of potential therapeutic candidates. Our verdicts contribute to the larger goal of finding effective cures for COVID-19, which is an acute global health challenge. The outcomes of our study provide valuable insights into potential therapeutic candidates for COVID-19 treatment.

PMID:40436944 | DOI:10.1038/s41598-025-02773-7

mSystems. 2025 May 28:e0019625. doi: 10.1128/msystems.00196-25. Online ahead of print.

ABSTRACT

Human microbiome plays a crucial role in host health and disease by mediating the impact of environmental factors on clinical outcomes. Mediation analysis is a valuable tool for dissecting these complex relationships. However, existing approaches are primarily designed for cross-sectional studies. Modern clinical research increasingly utilizes long follow-up periods, leading to complex data structures, particularly in metagenomic studies. To address this limitation, we introduce a novel mediation framework based on structural equation modeling that leverages linear mixed-effects models using penalized quasi-likelihood estimation with a debiased lasso. We applied this framework to a 16S rRNA sputum microbiome data set collected from patients with cystic fibrosis over 10 years to investigate the mediating role of the microbiome in the relationship between clinical states, disease aggressiveness phenotypes, and lung function. We identified richness as a key mediator of lung function. Specifically, Streptococcus was found to be significantly associated with mediating the decline in lung function on treatment compared to exacerbation, while Gemella was associated with the decline in lung function on recovery. This approach offers a powerful new tool for understanding the complex interplay between microbiome and clinical outcomes in longitudinal studies, facilitating targeted microbiome-based interventions.

IMPORTANCE: Understanding the mechanisms by which the microbiome influences clinical outcomes is paramount for realizing the full potential of microbiome-based medicine, including diagnostics and therapeutics. Identifying specific microbial mediators not only reveals potential targets for novel therapies and drug repurposing but also offers a more precise approach to patient stratification and personalized interventions. While traditional mediation analyses are ill-equipped to address the complexities of longitudinal metagenomic data, our framework directly addresses this gap, enabling robust investigation of these increasingly common study designs. By applying this framework to a decade-long cystic fibrosis study, we have begun to unravel the intricate relationships between the sputum microbiome and lung function decline across different clinical states, yielding insights that were previously unknown.

PMID:40434093 | DOI:10.1128/msystems.00196-25

Br J Clin Pharmacol. 2025 May 28. doi: 10.1002/bcp.70113. Online ahead of print.

ABSTRACT

This review highlights the role of reverse transcriptase (RT) inhibition in cellular regulation associated with non-terminal repeat retrotransposons and endogenous retroviruses. Based on their pleiotropic characteristics, RT inhibitors (RTIs) are discussed as potential anticancer agents. Both the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) display cytotoxicity in cancer cells which are likely mediated by endogenous RT inhibition and not necessarily by differing molecular structures. Three features of RTIs are evident in inducing cytotoxicity in cancer cells. Firstly, NRTIs and NNRTIs induce cell cycle arrest. Secondly, they suppress transposable elements, inhibit long interspersed nuclear elements (LINE)-1, with RTI key in cytotoxicity in cancer cells. Thirdly, the cyclic GMP-AMP-synthase-stimulator of interferon genes (cGAS-STING) pathway can be activated by LINE-1-derived cytoplasmic DNA with promotion of p21-dependent cell cycle arrest and cell-mediated immune response. This suggests that RTIs induce DNA strand breaks with incomplete retrotransposition, initiate cell cycle arrest and an immune response. Additionally, poly (ADP-ribose) polymerase 1 and 2 (PARP1, PARP2) and its relationship with DNA methylation is highlighted in the context of LINE-1 retrotransposition. There is a need to examine the relationship between PARP1, PARP2 and mutated BRCA proteins in normal and abnormal LINE-1 retrotransposition. This review explores how efavirenz and related RT inhibitors suppress endogenous reverse transcriptase, providing a basis for preclinical evaluation of RT inhibitors as potential repurposed drugs for cancer treatment.

PMID:40432477 | DOI:10.1002/bcp.70113

Viruses. 2025 May 18;17(5):722. doi: 10.3390/v17050722.

ABSTRACT

The COVID-19 pandemic has had a significant impact and continues to alarm the entire world due to the rapid emergence of new variants, even after mass vaccinations. There is still an urgent need for new antivirals or strategies to combat the SARS-CoV-2 infections; however, we have success stories with nirmatrelvir. Drug repurposing and drug discovery may lead to a successful SARS-CoV-2 antiviral; however, rapid drug use may cause unexpected mutations and antiviral drug resistance. Conversely, novel variants of the SARS-CoV-2 can diminish the neutralizing efficacy of vaccines, thereby enhancing viral fitness and increasing the likelihood of drug resistance emergence. Additionally, the disposal of antivirals in wastewater also contributes to drug resistance. Overall, the present review summarizes the strategies and mechanisms involved in the development of drug resistance in SARS-CoV-2. Understanding the mechanism of antiviral resistance is crucial to mitigate the significant healthcare threat and to develop effective therapeutics against drug resistance.

PMID:40431733 | DOI:10.3390/v17050722

Pharmaceutics. 2025 May 9;17(5):631. doi: 10.3390/pharmaceutics17050631.

ABSTRACT

Background/Objectives: Nanocarrier particle design for treating chronic pulmonary diseases presents several challenges, including anatomical and physiological barriers. Drug-repurposing technology using monodispersed spherical silica is one of the innovative ways to deliver drugs. In the present study, the anticancer potential of combinational cisplatin/ribavirin was explored for targeted lung cancer therapeutics. Methods: Monodispersed spherical silica (80 nm) capable of diffusing into the tracheal mucus region was chosen and doped with 10 wt% superparamagnetic iron oxide nanoparticles (SPIONs). Subsequently, it was wrapped with chitosan (Chi, 0.6 wt/vol%), functionalized with 5% wt/wt cisplatin (Cp)/ribavarin (Rib) and angiotensin-converting enzyme 2 (ACE-2) (1.0 μL/mL). Formulations are based on monodispersed spherical silica or halloysite and are termed as (S/MSSiO2/Chi/Cp/Rib) or (S/Hal/Chi/Cp/Rib), respectively. Results: X-ray diffraction (XRD) and diffuse reflectance UV-visible spectroscopy (DRS-UV-vis) analysis of S/MSSiO2/Chi/Cp/Rib confirmed the presence of SPION nanoclusters on the silica surface (45% coverage). The wrapping of chitosan on the silica was confirmed with a Fourier transformed infrared (FTIR) stretching band at 670 cm-1 and ascribed to the amide group of the polymer. The surface charge by zetasizer and saturation magnetization by vibrating sample magnetometer (VSM) were found to be -15.3 mV and 8.4 emu/g. The dialysis membrane technique was used to study the Cp and Rib release between the tumor microenvironment and normal pH ranges from 5.5 to 7.4. S/MSSiO2/Chi formulation demonstrated pH-responsive Cp and Rib at acidic pH (5.6) and normal pH (7.4). Cp and Rib showed release of ~27% and ~17% at pH 5.6, which decreases to ~14% and ~3.2% at pH 7.4, respectively. To assess the compatibility and cytotoxic effect of our nanocomposites, the cell viability assay (MTT) was conducted on cancer lung cells A549 and normal HEK293 cells. Conclusions: The study shows that the designed nanoformulations with multifunctional capabilities are able to diffuse into the lung cells bound with dual drugs and the ACE-2 receptor.

PMID:40430922 | DOI:10.3390/pharmaceutics17050631

Pharmaceutics. 2025 Apr 24;17(5):558. doi: 10.3390/pharmaceutics17050558.

ABSTRACT

Numerous anti-diabetic medications, including metformin, have been explored for their anticancer effects because of the substantial correlation between diabetes and cancer incidence. Metformin has recently gained interest for its anticancer effects against malignancies such as breast cancer, one of the leading causes of death among women worldwide. The cancer-related characteristics of cell proliferation, invasion, migration, and apoptosis are all targeted by metformin. Among breast cancer patients, triple-negative breast cancer (TNBC) is linked to an increased risk of early recurrence and metastases and has poor prognosis. In addition, TNBC has fewer treatment options compared to other breast cancer subtypes because it lacks hormone receptors and human epidermal growth factor receptor 2 (HER2), and it often develops resistance to available treatment options. The current review highlights the recent updates on the mechanistic insights and the efficacy of metformin and metformin-based approaches for the treatment of TNBC. We logically discuss the experimental evidence from the in vitro and in vivo studies exploring metformin's effects on metabolic pathways, and then its combination with other therapeutic agents, targeting cell signaling pathways, and approaches to enhance metformin's effects. We also present clinical studies that underscore the beneficial outcomes of metformin or its combination with other agents in TNBC patients.

PMID:40430851 | DOI:10.3390/pharmaceutics17050558

Pharmaceuticals (Basel). 2025 May 9;18(5):700. doi: 10.3390/ph18050700.

ABSTRACT

Neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's disease, due to their multifaced and complicated nature, remain uncurable and impose substantial financial and human burdens on society. Therefore, developing new innovative therapeutic strategies is vital. In this context, drug repurposing has emerged as a promising avenue to expedite the development of treatments for these challenging conditions. One particularly compelling target in this regard is the chaperone protein sigma-1 receptor (S1R), which has garnered significant attention for its neuroprotective properties. Interestingly, several medications, including fluvoxamine (an antidepressant), dextromethorphan (a cough suppressant), and amantadine (an antiviral), which were initially developed for unrelated indications, have shown encouraging results in neurodegenerative therapy through S1R activation. These findings suggest that existing drugs in pharmacopeias can play an essential role in alleviating neurodegenerative symptoms by modulating S1R, thereby offering a faster route and cost-effective path to clinical applications compared to the de novo development of entirely new compounds. Furthermore, as a synergistic benefit, combining S1R-targeting drugs with other therapeutic agents may also improve treatment efficacy. In this review, we highlight key repurposed drugs targeting S1R and explore their mechanisms of action, shedding light on their emerging therapeutic potential in the fight against neurodegeneration.

PMID:40430519 | DOI:10.3390/ph18050700

Pharmaceuticals (Basel). 2025 May 1;18(5):669. doi: 10.3390/ph18050669.

ABSTRACT

Background/Objectives: α-carbonic anhydrase (α-TcCA) has emerged as a promising drug target in T. cruzi, the causative agent of Chagas disease in the Americas. Sulfonamides, known inhibitors of CAs, bind to the zinc ion on the enzyme's active site. This study proposes the repositioning of sulfonamide-based drugs to identify new trypanocidal agents. Method: Ligand-based virtual screening and molecular docking analysis were performed on FDA-approved drugs targeting α-TcCA. These compounds were evaluated in vitro and ex vivo against the A1 and NINOA strains, followed by enzymatic assays. Results: Four sulfonylureas were selected: glimepiride (Glim), acetohexamide (Ace), gliclazide (Glic), and tolbutamide (Tol). Ace and Tol had half-maximal inhibitory concentration (IC50) values similar or better than reference drugs against the NINOA strain in the epimastigote and trypomastigote stages, while Glic and Glim had the highest activity against the A1 strain (epimastigotes and amastigotes). Notably, Ace had the highest trypanocidal activity against all stages in NINOA, with IC50 values of 6.5, 46.5, and 46 μM for epimastigotes, trypomastigotes, and amastigotes, respectively. Additionally, Ace inhibited α-TcCA with KI = 5.6 μM, suggesting that its trypanocidal effect is associated to the enzyme inhibition. Conclusions: This study supports the repositioning of FDA-approved sulfonamide-based hypoglycaemic agents as trypanocidal compounds. Future studies should focus on structural modifications to improve selectivity. Integrating docking, parasitological, and enzymatic data is crucial for optimizing drug candidates for Chagas disease.

PMID:40430488 | DOI:10.3390/ph18050669

Pharmaceuticals (Basel). 2025 Apr 23;18(5):613. doi: 10.3390/ph18050613.

ABSTRACT

Background: Oropouche virus (OROV), part of the Peribunyaviridae family, is an emerging pathogen causing Oropouche fever, a febrile illness endemic in South and Central America. Transmitted primarily through midge bites (Culicoides paraensis), OROV has no specific antiviral treatment or vaccine. This study aims to identify host-targeted therapeutics against OROV using computational approaches, offering a potential strategy for sustainable antiviral drug discovery. Methods: Virus-associated host targets were identified using the OMIM and GeneCards databases. The Enrichr and DSigDB platforms were used for drug prediction, filtering compounds based on Lipinski's rule for drug likeness. A protein-protein interaction (PPI) network analysis was conducted using the STRING database and Cytoscape 3.10.3 software. Four key host targets-IL10, FASLG, PTPRC, and FCGR3A-were prioritized based on their roles in immune modulation and OROV pathogenesis. Molecular docking simulations were performed using the PyRx software to evaluate the binding affinities of selected small-molecule inhibitors-Acetohexamide, Deptropine, Methotrexate, Retinoic Acid, and 3-Azido-3-deoxythymidine-against the identified targets. Results: The PPI network analysis highlighted immune-mediated pathways such as Fc-gamma receptor signaling, cytokine control, and T-cell receptor signaling as critical intervention points. Molecular docking revealed strong binding affinities between the selected compounds and the prioritized targets, suggesting their potential efficacy as host-targeting antiviral candidates. Acetohexamide and Deptropine showed strong binding to multiple targets, indicating broad-spectrum antiviral potential. Further in vitro and in vivo validations are needed to confirm these findings and translate them into clinically relevant treatments. Conclusions: This study highlights the potential of using computational approaches to identify host-targeted therapeutics for Oropouche virus (OROV). By targeting key host proteins involved in immune modulation-IL10, FASLG, PTPRC, and FCGR3A-the selected compounds, Acetohexamide and Deptropine, demonstrate strong binding affinities, suggesting their potential as broad-spectrum antiviral candidates. Further experimental validation is needed to confirm their efficacy and potential for clinical application, offering a promising strategy for sustainable antiviral drug discovery.

PMID:40430433 | DOI:10.3390/ph18050613

Int J Mol Sci. 2025 May 14;26(10):4701. doi: 10.3390/ijms26104701.

ABSTRACT

P-glycoprotein (P-gp), a transmembrane efflux pump encoded by the ABCB1/MDR1 gene, is a major contributor to multidrug resistance in hematological malignancies. These malignancies, arising from hematopoietic precursors at various differentiation stages, can manifest in the bone marrow, circulate in the bloodstream, or infiltrate tissues. P-gp overexpression in malignant cells reduces the efficacy of chemotherapeutic agents by actively expelling them, decreasing intracellular drug concentrations, and promoting multidrug resistance, a significant obstacle to successful treatment. This review examines recent advances in combating P-gp-mediated resistance, including the development of novel P-gp inhibitors, innovative drug delivery systems (e.g., nanoparticle-based delivery), and strategies to modulate P-gp expression or activity. These modulation strategies encompass targeting relevant signaling pathways (e.g., NF-κB, PI3K/Akt) and exploring drug repurposing. While progress has been made, overcoming P-gp-mediated resistance remains crucial for improving patient outcomes. Future research directions should prioritize the development of potent, selective, and safe P-gp inhibitors with minimal off-target effects, alongside exploring synergistic combination therapies with existing chemotherapeutics or novel agents to effectively circumvent multidrug resistance in hematological malignancies.

PMID:40429842 | DOI:10.3390/ijms26104701