Molecules. 2025 Jul 10;30(14):2925. doi: 10.3390/molecules30142925.

ABSTRACT

The repurposing potential of Efavirenz (EFV), a clinically established non-nucleoside reverse transcriptase inhibitor, was comprehensively evaluated for its in vitro antibacterial effect either alone or in combination with other antibacterial agents on several Gram-positive clinical strains showing different antibiotic resistance profiles. The binding potential assessed by an in silico study included Penicillin-binding proteins (PBPs) and WalK membrane kinase. Despite the relatively high minimum inhibitory concentration (MIC) limiting the use of EFV as a single antibacterial agent, it exhibits significant synergistic activity at sub-MIC levels when paired with various antibiotics against Enterococcus species and Staphylococcus aureus. EFV showed restored sensitivity of β-lactams against Methicillin-resistant S. aureus (MRSA). It increased the effectiveness of antibiotics tested against Methicillin-sensitive S. aureus (MSSA). It also helped to overcome the intrinsic resistance barrier for several antibiotics in Enterococcus spp. In silico binding studies aligned remarkably with experimental antimicrobial testing results and highlighted the potential of EFV to direct the engagement of PBPs with moderate to strong binding affinities (pKa 5.2-6.1). The dual-site PBP2 binding mechanism emerged as a novel inhibition strategy, potentially circumventing resistance mutations. Special attention should be paid to WalK binding predictions (pKa = 4.94), referring to the potential of EFV to interfere with essential regulatory pathways controlling cell wall metabolism and virulence factor expression. These findings, in general, suggest the possibility of EFV as a promising lead for the development of new antibacterial agents.

PMID:40733192 | DOI:10.3390/molecules30142925

Pharmaceuticals (Basel). 2025 Jul 14;18(7):1040. doi: 10.3390/ph18071040.

ABSTRACT

In the original publication [...].

PMID:40732369 | DOI:10.3390/ph18071040

Pharmaceuticals (Basel). 2025 Jun 27;18(7):972. doi: 10.3390/ph18070972.

ABSTRACT

Background: Skin cancer has become a global health issue because of increasing exposure to environmental contaminants and UV radiation. Terbinafine hydrochloride (TRB), a broad-spectrum antifungal medication, has demonstrated notable anti-tumor properties in previous studies; however, its repurposing for skin cancer therapy remains underexplored. Objective: This study reports for the first time, the development of a new delivery system: a nanoemulsion (NE)-foam hybrid system, i.e., "nanoemulfoam" (NEF), designed to enhance the topical TRB delivery to the skin. The study applied this new hybrid system on TRB for managing skin cancer. Method: The TRB-loaded NEF was produced by loading TRB into a liquid NE. then this was incorporated into a liquid foam base and actuated into foam using a non-propellant mechanism. The NE was developed utilizing peppermint oil as the oil phase and Tween-20/ethanol as the surfactant/co-surfactant combination (Smix). The formulation underwent optimization using the D-optimal design that enabled the simultaneous evaluation of the impact of oil concentration and Tween 20 concentration in the Smix on the particle size (PS), zeta potential (ZP), and dissolution efficiency percent (DE%). Results: The optimal NE formula displayed a small PS of 186.60 ± 2.84 nm, ZP of -13.90 ± 0.99 mV, and DE% of 68.50 ± 1.78% (mean ± SD, n = 3). After incorporation into the foam system, the produced TRB-loaded NEF demonstrated a 7.43-fold increase in the drug transdermal flux in comparison with plain drug foam (p < 0.05). The TRB-loaded NEF showed no signs of inflammation or irritation when applied to abdominal rabbit skin, indicating its safety. The optimum formula exhibited a statistically significant 10-fold increase in cytotoxicity against A-431 skin cancer cells compared to TRB alone, along with a 1.54-fold increase in apoptosis (p < 0.05). Molecular docking studies targeting CDK2, a key regulator of cell proliferation and a known TRB target, revealed that TRB displayed highly favorable binding scores compared to the reference drug. Conclusions: The TRB-loaded NEF represents a promising nanotechnology-based approach for the topical treatment of skin cancer, supporting further investigation toward clinical translation.

PMID:40732261 | DOI:10.3390/ph18070972

Pharmaceuticals (Basel). 2025 Jun 25;18(7):956. doi: 10.3390/ph18070956.

ABSTRACT

Background: Drug therapy remains the principal management strategy for malaria but is increasingly challenged by the emergence of drug-resistant malaria parasites. The need for new antimalarial drugs is urgent, yet drug discovery and development are hindered by high costs, long durations, and safety concerns that prevent approval. The current study aimed to determine antiplasmodial activities of approved drugs in combination with artemether (ART) and lumefantrine (LU). Methods: Using the SYBR Green I assay test, this study investigated the efficacy of epirubicin (EPI) and pelitinib (PEL) combined with ART and LU at fixed drug-drug ratios (4:1, 3:1, 1:1, 1:2, 1:3 and 1:4) and volume/volume. These combinations, as well as single drug treatments, were tested against cultured strains of Plasmodium falciparum (W2, DD2, D6, 3D7 and F32-ART) and fresh and cultured clinical isolates. The fifty percent inhibition concentration (IC50) and a mean sum of fifty percent fractional inhibition concentration (FIC50) were determined. Results: Synergism was observed when EPI was combined with both ART and LU across all fixed ratios with a mean of mean FIC50 values of <0.6. The combination of LU and EPI against the 3D7 strain demonstrated the highest efficacy with a synergism FIC50 value of 0.18. Most combinations of PEL with ART and LU showed antagonism (FIC50 > 1) when tested against strains of P. falciparum and clinical isolates. Conclusions: This study underscores the utility of alternative drug discovery and development strategies to bypass cost, time, and safety barriers, thereby enriching the antimalarial drug pipeline and accelerating the transition from lab to market.

PMID:40732245 | DOI:10.3390/ph18070956

Pharmaceuticals (Basel). 2025 Jun 20;18(7):936. doi: 10.3390/ph18070936.

ABSTRACT

Background: BCR-ABL inhibitors such as imatinib and nilotinib exhibit multi-kinase activity that extends beyond oncology, offering significant potential for drug repurposing. Objectives: This study aims to systematically evaluate and prioritize the repurposing potential of BCR-ABL inhibitors, particularly imatinib and nilotinib. Methods: An integrated pharmacoinformatics framework was applied to analyze seven BCR-ABL inhibitors. Structural clustering, cheminformatics analysis, and transcriptomic profiling using the Connectivity Map were employed to evaluate structural relationships, target profiles, and gene expression signatures associated with non-oncology indications. Results: Structurally, imatinib and nilotinib clustered closely, while HY-11007 exhibited distinct features. Nilotinib's high selectivity correlated with strong transcriptional effects in neurodegeneration-related pathways (e.g., HSP90 and LYN), whereas imatinib's broader kinase profile (PDGFR and c-KIT) was linked to fibrosis and metabolic regulation. Connectivity Map analysis identified more than 30 non-cancer indications, including known off-target uses (e.g., imatinib for pulmonary hypertension) and novel hypotheses (e.g., nilotinib for Alzheimer's via HSPA5 modulation). A substantial portion of these predictions aligned with the existing literature, underscoring the translational relevance of the approach. Conclusions: These findings highlight the importance of integrating structure-activity relationships and transcriptomic signatures to guide rational repurposing. We propose prioritizing nilotinib for CNS disorders and imatinib for systemic fibrotic diseases, supporting their advancement into preclinical and clinical evaluation. More broadly, this framework offers a versatile platform for uncovering hidden therapeutic potential across other drug classes with complex polypharmacology.

PMID:40732226 | DOI:10.3390/ph18070936

Int J Mol Sci. 2025 Jul 10;26(14):6628. doi: 10.3390/ijms26146628.

ABSTRACT

Malignant peripheral nerve sheath tumors (MPNSTs) are a rare type of soft tissue sarcoma associated with poor prognoses. The standard of care for non-resectable tumors consists of surgical excision followed by radiation and chemotherapy. MPNSTs are most common in patients with neurofibromatosis type 1 but can also occur sporadically. Regardless of origin, MPNSTs most often rely on signaling pathways that increase basal oxidative stress. This provides the basis for developing therapeutics with mechanisms that can potentiate oxidative stress to selectively eradicate tumor cells at doses that are tolerable for normal cells. Artemisinin derivatives are a mainstay of malaria therapy worldwide, with a well-established safety profile. Artemisinin's antimalarial effects are due to an endoperoxide bridge in its chemical structure that induces oxidative stress. We found that artesunate (ARS) and metabolite dihydroartemisinin (DHA) are selectively cytotoxic to MPNST cells relative to normal Schwann cells with the endoperoxide bridge required for activity. Mechanistically, DHA induced oxidative stress, lipid peroxidation, and DHA-mediated cytotoxicity could be prevented with co-administration of the antioxidant N-acetyl-cysteine. Furthermore, we found that DHA was able to selectively remove MPNST from co-culture with normal Schwann cells. These data supports the further development of artemisinins for the clinical management of MPNST.

PMID:40724874 | DOI:10.3390/ijms26146628

Curr Issues Mol Biol. 2025 Jun 27;47(7):496. doi: 10.3390/cimb47070496.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types due to its late diagnosis, low survival rates, and high frequency of metastasis. Considering the molecular mechanism of PDAC development has not been fully elucidated, this study aimed to shed more light on the molecular regulatory signatures of circular RNAs (circRNAs) in PDAC progression and provide a different perspective to identify potential biomarkers as well as discover candidate repositioned drug molecules for the prevention or treatment of PDAC with network-based integrative analysis. The mRNA, miRNA, and circRNA expression profiles of PDAC were obtained from nine microarray datasets. Differentially expressed genes (DEGs), microRNAs (DEmiRNAs), and circular RNAs (DEcircRNAs) were identified. The competing endogenous RNA (ceRNA; DEG-DEmiRNA-DEcircRNA) regulatory network was constructed, which included 12 DEcircRNAs, 64 DEGs, and 6 miRNAs specific to PDAC. The ADAM12, MET, QKI, SEC23A, and ZEB2 were identified as hub genes and demonstrated significant survival probability for PDAC. In addition to providing novel biomarkers for diagnosis that can be detected non-invasively, the secretion levels of hub genes-associated proteins were found in plasma, serum, and oral epithelium. The drug repositioning analysis revealed vorinostat, meclocycline sulfosalicylate, and trichostatin A, which exhibited significant binding affinities to the hub genes compared to their inhibitors via molecular docking analysis.

PMID:40728965 | DOI:10.3390/cimb47070496

Brief Bioinform. 2025 Jul 2;26(4):bbaf382. doi: 10.1093/bib/bbaf382.

ABSTRACT

Drug repositioning has become a hot topic that could provide an innovative solution in drug discovery by exploring the potential correlation between drugs and diseases. However, existing computational drug repositioning methods fail to effectively integrate heterogeneous data from multiple sources and neglect the multi-level and multi-scale interactions in biological systems. To address the above problems, we propose MAPTrans, which dynamically optimizes the representation of disease and drug with a multi-level meta-path aggregation strategy. In addition, a multi-view importance assessment mechanism is introduced to evaluate and filter the most discriminating views to optimize feature representation. A mutual attention mechanism Transformer architecture with a cross-view interaction that fuses the information of drugs and diseases in a multi-view space is designed. Experimental results of MAPTrans on multiple benchmark datasets show that it significantly outperforms existing baseline models.

PMID:40728860 | DOI:10.1093/bib/bbaf382

Front Psychiatry. 2025 Jul 14;16:1574458. doi: 10.3389/fpsyt.2025.1574458. eCollection 2025.

ABSTRACT

Schizophrenia (SCZ), Bipolar Disorder (BD), and Major Depressive Disorder (MDD) are severe psychiatric conditions that share overlapping clinical symptoms, yet they differ in their underlying molecular mechanisms. Despite extensive research, the biological foundations of these disorders remain incompletely understood. In this study, we performed a large-scale transcriptomic analysis by integrating 557 publicly available RNA-seq datasets from post-mortem brain tissues, spanning multiple regions, to better understand the shared and distinct molecular features of these disorders. Using systematic bioinformatic approaches, we identified differentially expressed genes (DEGs) and investigated associated biological pathways, regulatory transcription factors, and drug-gene interactions. Our analysis revealed notable overlap in gene expression profiles, particularly between SCZ and BD, suggesting common molecular pathways underlying these disorders. At the same time, each disorder also demonstrated unique transcriptional patterns, supporting the existence of disorder-specific mechanisms. Brain region-specific analyses further highlighted spatial heterogeneity in gene expression, with significant differences observed in regions such as the hippocampus and dorsolateral prefrontal cortex (DLPFC). The transcription factor enrichment analysis revealed distinct regulatory programs driving each disorder: MDD pathology appears regulated by ASCL3, MYOG, HNF1B, RUNX3, FOXA1 and STAT4; BD exhibited predominant control by immune-regulatory factors including FOSL1, FOSL2, PLSCR1, RELB, BATF3, IRF and NFKB1; while SCZ demonstrated unique regulation through ATF5, CREB3L3, SNAI1, NFIL3, CEBPB, RELB and IRF transcription factors. Moreover, our drug-gene interaction analysis uncovered promising therapeutic targets, with several differentially expressed genes showing potential for drug repurposing, particularly in relation to antipsychotics and immunomodulatory agents. Our comprehensive transcriptomic analysis reveals both shared molecular mechanisms and distinct immune signatures across schizophrenia, bipolar disorder, and major depressive disorder, advancing our understanding of psychiatric pathophysiology while highlighting the heterogeneous nature of these conditions. These findings establish a critical foundation for developing targeted, patient-specific therapeutic interventions that address the underlying biological complexity of major psychiatric disorders.

PMID:40727846 | PMC:PMC12301984 | DOI:10.3389/fpsyt.2025.1574458

J Exp Pharmacol. 2025 Jul 23;17:507-518. doi: 10.2147/JEP.S524226. eCollection 2025.

ABSTRACT

PURPOSE: The worldwide threat of herpes virus infections and their resistance against the existing drugs creates an urgent need for the development of novel drug candidates. An RNase H like domain is present in the protein encoded by the highly conserved ul15 gene (UL15) of Herpes Simplex Virus, ul89 gene encoded protein (UL89) of Human Cytomegalo Virus and Human Immunodeficiency Virus (HIV) integrase proteins. This provided a way repurpose HIV integrase inhibitors as HSV UL15 and HCMV UL89 inhibitors.

MATERIALS AND METHODS: The protein sequences were aligned using the Clustal Omega software to determine the conserved amino acid positions. Schrodinger software was used for docking studies, protein-ligand interaction and simulation studies. The selected drugs were screened to analyse their anti- HSV-1 and HSV-2 activities by Cytopathic effect (CPE) inhibition assay and RT-PCR using Vero cells as host. The experiments were further analyzed by the two-way ANOVA test using Bonferroni's post-HOC using GraphPad Prism software version 8.0.2. The RT-PCR experimental results were analyzed using the 2-∆∆Ct Livak method to determine the fold reduction in viral gene expression.

RESULTS: The in-silico studies showed the binding abilities of anti-HIV drugs to the active site of UL15 and UL89 by blocking their metal ions, similar to HIV integrase. Among the anti-HIV drugs tested, Elvitegravir and raltegravir were most effective in controlling the HSV-1 and HSV-2 infections at concentrations as low as 1.6 µg/mL when tested with 10TCID50 viral challenge dose. Elvitegravir was most effective in reducing the viral gene expression as tested by RT-PCR.

CONCLUSION: The tested FDA approved drug molecules showed the potential to be repurposed as an antiHSV and antiHCMV agent. The in silico and in vitro results warrant further investigation in preclinical and clinical studies to validate its therapeutic potential and safety for HSV-related infections.

PMID:40727394 | PMC:PMC12302220 | DOI:10.2147/JEP.S524226

Biofilm. 2025 Jul 16;10:100307. doi: 10.1016/j.bioflm.2025.100307. eCollection 2025 Dec.

ABSTRACT

Antimicrobial resistance (AMR) is a global concern that undermines microbial disease treatment and prevention. WHO and World Bank's EcoAMR report predicts that AMR could cause 39 million deaths and $3.4 trillion in annual GDP losses by the year 2050. This is particularly critical with S. aureus, a cause of diverse infections like skin abscesses and pneumonia, where antibiotic resistance increases mortality and hinders treatment. Biofilms are one of the major causes of multi-drug resistance in S. aureus, and their inhibition can restore antibiotic sensitivity. In this study, through screening of the LOPAC drug library, we identified several compounds that exhibit biofilm inhibitory properties against multi-drug-resistant S. aureus without affecting its growth. The compound 10058-F4 was found to have the strongest anti-biofilm activity (>70 % inhibition) with minimal antibacterial effects (MIC 256 μg/mL); however, it showed no inhibitory effects on pre-existing biofilm. Further, the 10058-F4 treatment suppressed the expression of sarA, the biofilm master regulator, along with biofilm genes, such as icaA, fnb, nuc, and sspA. Additionally, the results showed that 10058-F4 synergistically enhanced the antibacterial activity of norfloxacin and tetracycline, indicating its potential use as an adjunct to the existing antibiotic treatments. While these findings suggest the potential of 10058-F4 for clinical use, further investigations are necessary to elucidate its mechanism of action and optimize its application in combination therapies.

PMID:40726827 | PMC:PMC12302182 | DOI:10.1016/j.bioflm.2025.100307

Chem Biol Drug Des. 2025 Aug;106(2):e70162. doi: 10.1111/cbdd.70162.

ABSTRACT

Non-tuberculous mycobacteria (NTM) are opportunistic pathogens that lead to severe, persistent infections, particularly in immunocompromised or vulnerable individuals. Infection rates are rising worldwide, highlighting NTM as an increasing threat to public health. There are currently no specific drugs, and the recommended regimens are usually ineffective. This scenario underlines the urgent need to develop new strategies to effectively combat these infections in a more innovative way. However, the development of new drugs can be a lengthy process, often taking more than a decade to identify even a single active compound. Among the new strategies that can expedite this process is the repurposing of approved drugs. In this work, we applied this approach to identify compounds inhibiting iron uptake in Mycobacterium abscessus (Mab). Specifically, we studied the targeting of salicylate synthase, an enzyme that plays a crucial role in the biosynthesis of mycobacterial siderophores necessary for iron acquisition. Performing an in silico virtual screening of three databases against the crystal structure of salicylate synthase, we identified 11 potential ligands. Then, in vitro assays on the recombinant enzyme highlighted three competitive inhibitors, namely fostamatinib, esomeprazole, and hydroxystilbamidine. These results confirm the potential of the repurposing approach and pave the way for further experimental validation and optimization of these inhibitors as promising compounds against NTM infections.

PMID:40726305 | DOI:10.1111/cbdd.70162

Int J Mol Sci. 2025 Jul 20;26(14):6984. doi: 10.3390/ijms26146984.

ABSTRACT

Cellular senescence is a state of the durable cell cycle arrest of dysfunctional cells, which has been associated with the promotion of tumor cell reprogramming into a stem cell state. We previously reported that the mixed lineage kinase (MLK) inhibitor CEP-1347 promotes the differentiation of glioma stem cells (GSCs)-key contributors to glioblastoma recurrence and therapy resistance-into non-stem tumor cells. However, we also noted that CEP-1347-treated GSCs exhibited a morphological change suggestive of senescence. Therefore, we herein investigated whether CEP-1347 induces senescence in GSCs and, consequently, if senescent GSCs may be eliminated using senolytics. Cell death induced by CEP-1347 in combination with senolytic agents or with the knockdown of anti-apoptotic BCL2 family genes, as well as the effects of CEP-1347 on the expression of senescence markers and anti-apoptotic Bcl-2 family proteins, were examined. The results obtained showed that CEP-1347 induced senescence in GSCs accompanied by the increased expression of Bcl-xL. Among the panel of senolytic agents tested, navitoclax, a BH3 mimetic, efficiently induced cell death in GSCs when combined with CEP-1347 at concentrations clinically achievable in the brain. The knockdown of Bcl-xL resulted in more pronounced GSC death in combination with CEP-1347 than that of Bcl-2. These results suggest that combining CEP-1347 with the targeting of Bcl-xL, the expression of which increases with CEP-1347-induced senescence, is a rational approach to ensure the elimination of GSCs, thereby improving the outcomes of glioblastoma treatment.

PMID:40725230 | DOI:10.3390/ijms26146984

Int J Mol Sci. 2025 Jul 15;26(14):6761. doi: 10.3390/ijms26146761.

ABSTRACT

The recent global coronavirus pandemic highlighted the ever-present threat of respiratory virus outbreaks and the consequent need for ongoing research into antiviral therapy. To this end, structural analogues of the guanidinium-based drug camostat mesylate have been synthesised to probe their potential inhibition of Transmembrane Serine Protease 2 (TMPRSS2), a human protease that is essential for infection by many respiratory viruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Our in vitro fluorescence-based protease assays and supporting computational docking studies suggest that C-terminal camostat analogues retain TMPRSS2 inhibition potencies (IC50 = 1-3 nM, BE = -6.6 to -7.0 kcal/mol) that match or exceed that of the parent drug. Analogues 1c and 1d emerge as lead candidates in this regard, thereby validating the rationale behind C-terminal structural modifications and highlighting these derivatives as promising scaffolds for the future development of targeted antiviral therapeutics. Replacement of camostat's ester functionality with peptide linkages largely preserves non-covalent binding but disrupts in vitro protease inhibition, findings consistent with the parent drug's known role as an acylating suicide inhibitor. Docking studies confirm that the replacement of aromatic residues with flexible, equivalent-length alkyl chains is detrimental to drug binding. These function and binding data offer new directions for the synthesis of further analogues of camostat and of other guanidinium-based protease inhibitors that have yet to be refined via structure-activity relationship studies. Further investigation will support tailoring this class of drugs for repurposing in antiviral therapy.

PMID:40725007 | DOI:10.3390/ijms26146761

Life (Basel). 2025 Jul 12;15(7):1097. doi: 10.3390/life15071097.

ABSTRACT

Neuro-oncology focuses on the diagnosis and treatment of brain tumors, which, despite their rarity, are associated with high mortality due to their invasiveness and limited treatment options. Emerging evidence suggests that dopamine (DA), a neurotransmitter crucial for cognitive and emotional processes, and its receptors may influence tumor growth and the tumor microenvironment. This study aimed to evaluate the potential anticancer effects of repurposed antipsychotic dopamine-targeting drugs (Clozapine, CLZ; Pimozide, PIM; Olanzapine, OLZ; and Risperidone, RIS) and antiemetic drugs (Domperidone, DOM; Droperidol, DRO) on neuroblastoma (SH-SY5Y) and glioblastoma (A172) cell lines, and to assess whether their efficacy is modulated by oxidative stress and DA synthesis. The drugs were first tested individually, followed by co-treatment with tyrosine (Tyr), a dopamine precursor, and hydrogen peroxide (H2O2), an inducer of oxidative stress. Additionally, drug activity was evaluated in the simultaneous presence of H2O2 and Tyr. CLZ exhibited the highest cytotoxicity in both cell lines, suggesting strong anticancer potential and also synergism among the different combinations, particularly in SH-SY5Y. Liquid chromatography of the extracellular medium showed greater Tyr consumption in SH-SY5Y compared to A172 cells, indicating a higher dependence on extracellular Tyr to mitigate drug- and/or stress-induced cytotoxicity. In summary, several of the repurposed antipsychotics demonstrated cytotoxic effects on central nervous system tumor cells, with CLZ showing the most promising activity, even under oxidative stress conditions. These findings support further investigation into dopamine-targeting drugs as potential therapeutic agents in neuro-oncology.

PMID:40724598 | DOI:10.3390/life15071097

Biomedicines. 2025 Jul 13;13(7):1709. doi: 10.3390/biomedicines13071709.

ABSTRACT

Diabetic neuropathy (DN) remains a major clinical burden, characterized by progressive sensory dysfunction, pain, and impaired quality of life. Despite the available symptomatic treatments, there is a pressing need for disease-modifying therapies. In recent years, preclinical research has highlighted the potential of repurposed pharmacological agents, originally developed for other indications, to target key mechanisms of DN. This narrative review examines the main pathophysiological pathways involved in DN, including metabolic imbalance, oxidative stress, neuroinflammation, ion channel dysfunction, and mitochondrial impairment. A wide array of repurposed drugs-including antidiabetics (metformin, empagliflozin, gliclazide, semaglutide, and pioglitazone), antihypertensives (amlodipine, telmisartan, aliskiren, and rilmenidine), lipid-lowering agents (atorvastatin and alirocumab), anticonvulsants (topiramate and retigabine), antioxidant and neuroprotective agents (melatonin), and muscarinic receptor antagonists (pirenzepine, oxybutynin, and atropine)-have shown promising results in rodent models, reducing neuropathic pain behaviors and modulating underlying disease mechanisms. By bridging basic mechanistic insights with pharmacological interventions, this review aims to support translational progress toward mechanism-based therapies for DN.

PMID:40722780 | DOI:10.3390/biomedicines13071709

Biomedicines. 2025 Jul 10;13(7):1687. doi: 10.3390/biomedicines13071687.

ABSTRACT

Background: Diabetic foot ulcers (DFUs) are a severe complication of diabetes and are characterized by impaired wound healing and a high amputation risk. Exosomes-which are nanovesicles carrying proteins, RNAs, and lipids-mediate intercellular communication in wound microenvironments, yet their biomarker potential in DFUs remains underexplored. Methods: We analyzed transcriptomic data from GSE134431 (13 DFU vs. 8 controls) as a training set and validated findings in GSE80178 (6 DFU vs. 3 controls). A sum of 7901 differentially expressed genes (DEGs) of DFUs were detected and intersected with 125 literature-curated exosome-related genes (ERGs) to yield 51 candidates. This was followed by GO/KEGG analyses and a PPI network construction. Support vector machine-recursive feature elimination (SVM-RFE) and the Boruta random forest algorithm distilled five biomarkers (DIS3L, EXOSC7, SDC1, STX11, SYT17). Expression trends were confirmed in both datasets. Analyses included nomogram construction, functional and correlation analyses, immune infiltration, GSEA, gene co-expression and regulatory network construction, drug prediction, molecular docking, and RT-qPCR validation in clinical samples. Results: A nomogram combining these markers achieved an acceptable calibration (Hosmer-Lemeshow p = 0.0718, MAE = 0.044). Immune cell infiltration (CIBERSORT) revealed associations between biomarker levels and NK cell and neutrophil subsets. Gene set enrichment analysis (GSEA) implicated IL-17 signaling, proteasome function, and microbial infection pathways. A GeneMANIA network highlighted RNA processing and vesicle trafficking. Transcription factor and miRNA predictions uncovered regulatory circuits, and DGIdb-driven drug repurposing followed by molecular docking identified Indatuximab ravtansine and heparin as high-affinity SDC1 binders. Finally, RT-qPCR validation in clinical DFU tissues (n = 5) recapitulated the bioinformatic expression patterns. Conclusions: We present five exosome-associated genes as novel DFU biomarkers with diagnostic potential and mechanistic links to immune modulation and vesicular transport. These findings lay the groundwork for exosome-based diagnostics and therapeutic targeting in DFU management.

PMID:40722759 | DOI:10.3390/biomedicines13071687

Biomedicines. 2025 Jul 9;13(7):1686. doi: 10.3390/biomedicines13071686.

ABSTRACT

Rafoxanide, originally developed as a veterinary anthelmintic for the treatment of parasitic infections in livestock, has recently emerged as a promising therapeutic prospect in oncology. This compound has demonstrated notable antineoplastic effects against a variety of cancers, including skin, gastric, colorectal, and lung cancers, as well as hematological malignancies such as multiple myeloma. Rafoxanide exerts its anticancer activity through multiple complementary mechanisms, including the induction of endoplasmic reticulum stress, cell cycle arrest, apoptosis, and immunogenic cell death. Furthermore, the drug has been reported to inhibit key oncogenic signaling pathways (e.g., STAT3, NF-κB, c-FLIP, survivin) that contribute to tumor growth and metastasis. Preclinical studies in murine models have demonstrated significant reductions in tumor volume of up to 50% and a tumor-free rate exceeding 80%, with effective doses ranging from 7.5 to 40 mg/kg. This multitargeted mode of action distinguishes rafoxanide from conventional therapies and may help overcome resistance mechanisms that often limit the efficacy of cancer treatments. In this review, we summarize and discuss the growing body of evidence supporting rafoxanide's therapeutic potential in oncology, as well as its possible applications in cancer treatment.

PMID:40722758 | DOI:10.3390/biomedicines13071686

Biomedicines. 2025 Jul 7;13(7):1654. doi: 10.3390/biomedicines13071654.

ABSTRACT

Precision medicine is transforming hematologic cancer care by tailoring treatments to individual patient profiles and moving beyond the traditional "one-size-fits-all" model. This review outlines foundational technologies, disease-specific advances, and emerging directions in precision hematology. The field is enabled by molecular profiling techniques, including next-generation sequencing (NGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), as well as epigenomic and proteomic analyses. Complementary tools such as liquid biopsy and minimal residual disease (MRD) monitoring have improved diagnosis, risk stratification, and therapeutic decision making. We discuss major molecular targets and personalized strategies across hematologic malignancies: FLT3 and IDH1/2 in acute myeloid leukemia (AML); Philadelphia chromosome-positive and Ph-like subtypes in acute lymphoblastic leukemia (ALL); BCR-ABL1 in chronic myeloid leukemia (CML); TP53 and IGHV mutations in chronic lymphocytic leukemia (CLL); molecular subtypes and immune targets in diffuse large B-cell lymphoma (DLBCL) and other lymphomas; and B-cell maturation antigen (BCMA) in multiple myeloma. Despite significant progress, challenges remain, including high costs, disparities in access, a lack of standardization, and integration barriers in clinical practice. However, advances in single-cell sequencing, spatial transcriptomics, drug repurposing, immunotherapies, pan-cancer trials, precision prevention, and AI-guided algorithms offer promising avenues to refine treatment and improve outcomes. Overcoming these barriers will be critical for ensuring the equitable and widespread implementation of precision medicine in routine hematologic oncology care.

PMID:40722725 | DOI:10.3390/biomedicines13071654

Biochem Pharmacol. 2025 Jul 26:117191. doi: 10.1016/j.bcp.2025.117191. Online ahead of print.

ABSTRACT

The antimalarial agent Dihydroartemisinin (DHA) has significant potential for drug repurposing for cancer therapy including non-small cell lung cancer (NSCLC). However, its underlying anti-tumor mechanisms remain to be elucidated. In this study, we demonstrated that DHA suppressed the mouse double minute 2 (MDM2) in A549 and H1299 cells, whereas MDM2 overexpression effectively restored DHA's inhibition on both NSCLC cell lines. We showed that DHA acted via phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and Janus kinase (JAK)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathways to inhibit MDM2 expression. Being an established MDM2 target, p53 was significantly upregulated in p53 wild-type A549 cells upon DHA treatment both in vitro and in vivo; however, the mediating role of MDM2 in DHA's suppression on NSCLC is independent of p53 since DHA-treated si-p53 A549 cells had comparable colony formation capacity compared with that of si-Control. The anti-tumor effects of DHA bypass p53 was further implicated using H1299, a cell line which is MDM2-overexpressed but p53-null. Instead, c-Myc was observed to mediate the effects of DHA/MDM2 axis as co-immunoprecipitation (Co-IP) analysis showed the direct protein interaction between MDM2 and c-Myc, both were substantially reduced upon DHA treatment. Furthermore, c-Myc overexpression effectively restored DHA's suppression on proliferation, and DHA's induction on apoptosis of A549 and H1299 cells. Finally, immunohistochemistry (IHC) analysis showed that in vivo administration of DHA substantially reduced both MDM2 and c-Myc expression in xenograft murine models. Taken together, our results demonstrated that DHA inhibits NSCLC by targeting MDM2/c-Myc axis independent of p53.

PMID:40721007 | DOI:10.1016/j.bcp.2025.117191